Pharmaceutically active compounds

ABSTRACT

Compounds of the formula (1):  
                 
 
     wherein R 1 , R 2 , R 4  and R 13  are as defined or a pharmaceutically or veterinarily acceptable salt or polymorph thereof, or a pharmaceutically or veterinarily acceptable solvate or pro-drug thereof: are potent and selective inhibitors of type 5 cyclic guanosine 3′,5′-monophosphate phosphodiestbrase (cGMP PDE5) and have utility in the treatment of, inter alia, male erectile dysfunction (MED) and female sexual dysfunction (FSD).

[0001] This invention relates to a series ofpyrazolo[4,3-d]pyrimidin-7-ones, which inhibit cyclic guanosine3′,5′-monophosphate phosphodiesterases (cGMP PDEs). More notably, thecompounds of the invention are potent and selective inhibitors of type 5cyclic guanosine 3′,5′-monophosphate phosphodiesterase (cGMP PDE5) andhave utility therefore in a variety of therapeutic areas.

[0002] The compounds of the invention are of value for the curative orprophylactic treatment of mammalian sexual disorders. In particular, thecompounds are of value in the treatment of mammalian sexual dysfunctionssuch as male erectile dysfunction (MED), impotence, female sexualdysfunction (FSD), clitoral dysfunction, female hypoactive sexual desiredisorder, female sexual arousal disorder, female sexual pain disorder orfemale sexual orgasmic dysfunction (FSOD) as well as sexual dysfunctiondue to spinal cord injury or selective serotonin re-uptake inhibitor(SSRI) induced sexual dysfunction but, clearly, will be useful also fortreating other medical conditions for which a potent and selective cGMPPDE5 inhibitor is indicated. Such conditions include premature labour,dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outletobstruction, incontinence, stable, unstable and variant (Prinzmetal)angina, hypertension, pulmonary hypertension, chronic obstructivepulmonary disease, coronary artery disease, congestive heart failure,atherosclerosis, conditions of reduced blood vessel patency, e.g.post-percutaneous transluminal coronary angioplasty (post-PTCA),peripheral vascular disease, stroke, nitrate induced tolerance,bronchitis, allergic asthma, chronic asthma, allergic rhinitis, diseasesand conditions of the eye such as glaucoma, optic neuropathy, maculardegeneration, elevated intra-occular pressure, retinal or arterialocculsion and diseases characterised by disorders of gut motility, e.g.irritable bowel syndrome (IBS).

[0003] Further medical conditions for which a potent and selective cGMPPDE5 inhibitor is indicated, and for which treatment with compounds ofthe present invention may be useful include pre-eclampsia, Kawasaki'ssyndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy,neuropathy including autonomic and peripheral neuropathy and inparticular diabetic neuropathy and symptoms thereof e.g. gastroparesis,peripheral diabetic neuropathy, Alzheimer's disease, acute respiratoryfailure, psoriasis, skin necrosis, cancer, metastasis, baldness,nutcracker oesophagus, anal fissure, haemorrhoids, hypoxicvasoconstriction as well as the stabilisation of blood pressure duringhaemodialysis.

[0004] Particularly preferred conditions include MED and FSD.

[0005] PCT application PCT/IB99/00519 relates to a series ofpyrazolo[4,3-d]pyrimidin-7-ones, which inhibit cyclic guanosine3′,5′-monophosphate phosphodiesterases (cGMP PDEs).

[0006] Thus the present invention provides compounds of the formula (I):

[0007] or a pharmaceutically or veterinarily acceptable salt thereof, ora pharmaceutically or veterinarily acceptable solvate of either entity,wherein

[0008] R¹ is C₁ to C₆ alkyl or C₃ to C₆ alkenyl, C₃ to C₆ cycloalkyl orC₄ to C₆ cycloalkenyl wherein said alkyl group may be branched orstraight chain and wherein

[0009] when R¹ is C₁ to C₃ alkyl said alkyl group is substituted by;

[0010] and wherein when R¹ is C₄ to C₆ alkyl, C₃ to C₆ alkenyl or C₃ toC₆ cycloalkyl said alkyl, alkenyl or cycloalkyl group is optionallysubstituted by;

[0011] one or more substituents selected from:

[0012] hydroxy;

[0013] C₁ to C₄ alkoxy;

[0014] C₃ to C₆ cycloalkyl;

[0015] phenyl substituted with one or more substitutents selected fromC₁ to C₃ alkyl, C₁ to C₄ alkoxy, C₁ to C₄ haloalkyl, C₁ to C₄haloalkoxy, halo, CN, NO, NHR¹¹, NHCOR¹², NHSOR¹², SOR¹², SO₂NHR¹, COR¹¹or CO₂R¹¹ wherein said haloalkyl and haloalkoxy groups contain one ormore halo atoms;

[0016] NR⁷R⁸, CONR⁷R⁸ or NR⁷COR¹¹ wherein R⁷ and R⁸ are eachindependently selected from H, C₁ to C₄ alkyl, C₃ to C₄ alkenyl, CO₂R⁹or SO₂R⁹ and wherein said alkyl or alkenyl groups are optionallysubstituted by C₁ to C₄ haloalkyl or C₁ to C₄ haloalkoxy;

[0017] Het¹;

[0018] Het2 or Het³;

[0019] or R¹ is Het⁴ or phenyl wherein said phenyl group is optionallysubstituted by one or more substituents selected from C₁ to C₄ alkyl, C₃to C₄ alkenyl, C₁ to C₄ alkoxy, halo, CN, CF₃, OCF₃, NO₂, NHR¹¹,NHCOR¹², NHSO₂R¹², SO₂R¹², SO₂NHR¹¹, COR¹¹ CO₂R¹¹;

[0020] R² is C₁ to C₆ alkyl, C₃ to C₆ alkenyl or (CH₂)_(n)(C₃ to C₆cycloalkyl) wherein n is 0, 1 or 2;

[0021] R¹³ is OR³ or NR⁵R⁶;

[0022] R³ is C₁ to C₆ alkyl optionally substituted with one or twosubstituents selected from C₃ to C₅ cycloalkyl, hydroxy, C₁ to C₄alkoxy, benzyloxy, NR⁵R⁶, phenyl, Het¹, Het², Het³ or Het⁴ wherein theC₁ to C₆ alkyl and C₁ to C₄ alkoxy groups may optionally be terminatedby a haloalkyl group such as CF₃ and wherein the C₃-C₅ cycloalkyl groupmay optionally be substituted by C₁-C₄ alkyl, hydroxy or halo; C₃ to C₆cycloalkyl; Het¹, Het², Het³ or Het⁴;

[0023] R⁴ is a piperazin-1-ylsulphonyl group having a substituent R¹⁰ atthe 4-position of the piperazinyl group wherein said piperazinyl groupis optionally substituted with one or two C₁ to C₄ alkyl groups and isoptionally in the form of its 4-N-oxide;

[0024] R⁵ and R⁶ are each independently selected from H and C₁ to C₄alkyl optionally substituted with C₃ to C₅ cycloalkyl or C₁ to C₄alkoxy, or, together with the nitrogen atom to which they are attached,form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group;

[0025] R⁷ and R⁸ are each independently selected from H, C₁ to C₄ alkyl,C₃ to C₄ alkenyl, CO₂R⁹ or SO₂R⁹;

[0026] R⁹ is C₁ to C₄ alkyl optionally substituted with C₁ to C₄haloalkyl, C₁ to C₄ haloalkoxy or phenyl wherein said phenyl group isoptionally substituted by one or more substituents selected from C₁ toC₄ alkyl optionally substituted by C₁ to C₄ haloalkyl or C₁ to C₄haloalkoxy, C₁ to C₄ alkoxy, halo, CN, NO₂, NHR¹¹, NHCOR¹², NHSO₂R¹²,SO₂R¹², SO₂NHR¹¹, COR¹¹ or CO₂R¹¹;

[0027] R¹⁰ is H; C₁ to C₄ alkyl optionally substituted with one or twosubstituents selected from hydroxy, NR⁵R⁶, CONR⁵R⁶, phenyl optionallysubstituted with C₁ to C₄ alkyl or C₁ to C₄ alkoxy; C₃ to C₆ alkenyl orHet⁴;

[0028] R¹¹ is H, C₁ to C₄ alkyl, C₃ to C₄ alkenyl, CO(C₁ to C₄ alkyl) orC₁ to C₄ haloalkyl;

[0029] R¹² is C₁ to C₄ alkyl, C₃ to C₄ alkenyl, C₁ to C₄ haloalkyl or C₁to C₄ haloalkoxy;

[0030] Het¹ is an N-linked 4-, 5- or 6-membered nitrogen-containingheterocyclic group optionally containing one or more further heteroatomsselected from S, N or O;

[0031] Het² is a C-linked 5-membered heterocyclic group containing an O,S or N heteroatom optionally containing one or more heteroatoms selectedfrom N, O or S;

[0032] Het³ is a C-linked 6-membered heterocyclic group containing an Oor S heteroatom optionally containing one or more heteroatoms selectedfrom O, S or N or Het³ is a C-linked 6-membered heterocyclic groupcontaining three N heteroatoms;

[0033] Het⁴ is a C-linked 4-, 5- or 6-membered heterocyclic groupcontaining one, two or three heteroatoms selected from S, O or N; and

[0034] wherein any of said heterocyclic groups Het¹, Het², Het³ or Het⁴may be saturated, partially unsaturated or aromatic and wherein any ofsaid heterocyclic groups may be optionally substituted with one or moresubstituents selected from C₁ to C₄ alkyl, C₃ to C₄ alkenyl, C₁ to C₄alkoxy, halo, CF₃, CO₂R¹¹, COR¹¹, SO₂R¹², NHR¹¹ or NHCOR¹² and/orwherein any of said heterocyclic groups is benzo-fused;

[0035] with the provisos that (a) when R¹ is C₁ to C₃ alkyl then Het¹ isnot morpholinyl or piperidinyl and (b) when R¹ is C₁ to C₃ alkylsubstituted by phenyl then said phenyl group is not substituted by C₁ toC₄ alkoxy, halo, CN, CF₃, OCF₃ or C₁ to C₄ alkyl.

[0036] As will be recognised by the skilled chemist, the general formula(I) can be represented by the regio-isomeric general formulae (IA) and(IB). Thus the present invention provides compounds of formulae (IA) and(IB):

[0037] wherein R¹, R², R⁴ and R¹³ are as defined hereinbefore.

[0038] In the above definitions, unless otherwise indicated, alkyl,alkoxy and alkenyl groups having three or more carbon atoms, andalkanoyl groups having four or more carbon atoms, may be straight chainor branched chain. For example, a C₄ alkyl substituent can be in theform of normal-butyl (n-butyl), iso-butyl (i-butyl), secondary-butyl(sec-butyl) or tertiary-butyl (t-butyl). The term halo atom includes Cl,Br, F, and 1. Haloalkyl and haloalkoxy are preferably —CF₃ and —OCF₃respectively. The term aromatic as defined herein means a fullyunsaturated system.

[0039] A compound of the formula (I) contains one or more asymmetriccarbon atoms and therefore exists in two or more stereoisomeric forms.Where a compound of the formula (I) contains an alkenyl or alkenylenegroup, cis (E) and trans (Z) isomerism may also occur. The presentinvention includes the individual stereoisomers of the compounds of theformula (I) and, where appropriate, the individual tautomeric formsthereof, together with mixtures thereof. Separation of diastereoisomersor cis and trans isomers may be achieved by conventional techniques,e.g. by fractional crystallisation, chromatography or H.P.L.C. of astereoisomeric mixture of a compound of the formula (I) or a suitablesalt or derivative thereof. An individual enantiomer of a compound ofthe formula (I) may also be prepared from a corresponding optically pureintermediate or by resolution, such as by H.P.L.C. of the correspondingracemate using a suitable chiral support or by fractionalcrystallisation of the diastereoisomeric salts formed by reaction of thecorresponding racemate with a suitable optically active acid or base, asappropriate.

[0040] All stereoisomers are included within the scope of the invention.

[0041] The compounds of formulae (IA) and (IB) may also exist intautomeric forms and the invention includes both mixtures thereof andthe individual tautomers.

[0042] Also included in the invention are radiolabelled derivatives ofcompounds of formulae (I), (IA) and (IB) which are suitable forbiological studies.

[0043] The pharmaceutically or veterinarily acceptable salts of thecompounds of the invention which contain a basic centre are, forexample, non-toxic acid addition salts formed with inorganic acids suchas hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid,with carboxylic acids or with organo-sulphonic acids. Examples includethe HCl, HBr, HI, sulphate or bisulphate, nitrate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, saccarate, fumarate, maleate,lactate, citrate, tartrate, gluconate, camsylate, methanesulphonate,ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoatesalts. Compounds of the invention can also provide pharmaceutically orveterinarily acceptable metal salts, in particular non-toxic alkali andalkaline earth metal salts, with bases. Examples include the sodium,potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.For a review on suitable pharmaceutical salts see Berge et al, J. Pharm,Sci., 66, 1-19, 1977.

[0044] The pharmaceutically acceptable solvates of the compounds of theinvention include the hydrates thereof.

[0045] Also included within the scope of the compound and various saltsof the invention are polymorphs thereof.

[0046] A preferred group of compounds of formulae (I), (IA) and (IB) isthat wherein, R¹ is C₁ to C₆ alkyl or C₃ to C₆ alkenyl wherein saidalkyl or alkenyl groups may be branched chain or straight chain or R¹ isC₃ to C₆ cycloalkyl or C₄ to C₆ cycloalkenyl

[0047] and wherein when R¹ is C₁ to C₃ alkyl said alkyl group issubstituted by; and wherein when R¹ is C₄ to C₆ alkyl, C₃ to C₆ alkenyl,C₃ to C₆ cycloalkyl or C₄ to C₆ cycloalkenyl said alkyl, alkenyl,cycloalkyl or cycloalkenyl group is optionally substituted by;

[0048] one or more substituents selected from:

[0049] hydroxy;

[0050] C₁ to C₄ alkoxy;

[0051] C₃ to C₄ cycloalkyl;

[0052] phenyl substituted with one or more substitutents selected fromC₁ to C₃ alkyl, C₁ to C₄ alkoxy, C₁ to C₄ haloalkyl or C₁ to C₄haloalkoxy, halo, CN, NO₂, NHR¹¹, NHCOR¹², NHSO₂R¹², SO₂R¹², SO₂NHR¹¹,COR¹¹, CO₂R¹¹ wherein said haloalkyl and haloalkoxy groups contain oneor more halo atoms;

[0053] NR⁷R⁸, CONR⁷R⁸ or NR⁷COR¹¹;

[0054] a Het¹ group which is an N-linked 4-membered N-containingheterocyclic group;

[0055] a Het² group which is a C-linked 5-membered heterocyclic groupcontaining an O, S or N heteroatom optionally containing one or moreheteroatoms selected from N, O or S;

[0056] a Het³ group which is a C-linked 6-membered heterocyclic groupcontaining an O or S heteroatom optionally containing one or moreheteroatoms selected from O, S or N or a Het³ group which is a C-linked6-membered heterocyclic group containing three N heteroatoms;

[0057] wherein R⁷, R⁸, R¹¹ and R¹² are as previously defined herein

[0058] or R¹ is a Het⁴ group which is a C-linked 4- or 5-memberedheterocyclic group containing one heteroatom selected from S, O or N; aHet⁴ group which is a C-linked 6-membered heterocyclic group containingone, two or three heteroatoms selected from S or O; a Het⁴ group whichis a C-linked 6-membered heterocyclic group containing three nitrogenheteroatoms; a Het⁴ group which is a C-linked 6-membered heterocyclicgroup containing one or two nitrogen heteroatoms which is substituted byone or more substitutents selected from C₁ to C₄ alkyl, C₁ to C4 alkoxy,CO₂R¹¹, SO₂R¹², COR¹¹, NHR¹¹ or NHCOR¹² and optionally including afurther heteroatom selected from S, O or N

[0059] wherein any of said heterocyclic groups Het¹, Het², Het³ or Het⁴is saturated, partially unsaturated or aromatic as appropriate andwherein any of said heterocyclic groups is optionally substituted withone or more substituents selected from C₁ to C₄ alkyl, C₃ to C₄ alkenyl,C₁ to C₄ alkoxy, halo, CO₂R¹¹, SO₂R¹², COR¹¹ or NHR¹¹ wherein R¹¹ is asdefined hereinbefore and/or wherein any of said heterocyclic groups isbenzo-fused;

[0060] or R¹ is phenyl substituted by one or more substituents selectedfrom CF₃, OCF₃, SO₂R¹² or CO₂R¹² wherein R¹² is C₁ to C₄ alkyl which isoptionally substituted by phenyl, C₁ to C₄ haloalkyl or C₁ to C₄haloalkoxy wherein said haloalkyl and haloalkoxy groups contain one ormore halo atoms;

[0061] R² is C₁ to C₆ alkyl;

[0062] R¹³ is OR³;

[0063] R³ is C₁ to C₆ alkyl optionally substituted with one or twosubstituents selected from C₃ to C₅ cycloalkyl, hydroxy, C₁ to C₄alkoxy, benzyloxy, NR⁵R⁶, phenyl, furanyl, tetrahydrofuranyl orpyridinyl wherein said C₁ to C₆ alkyl and C₁ to C₄ alkoxy groups mayoptionally be terminated by a haloalkyl group such as CF₃; or R³ is C₃to C₆ cycloalkyl, 1-(C₁ to C₄ alkyl)piperidinyl, tetrahydrofuranyl ortetrahydropyranyl;

[0064] R⁴ is a piperazin-1-ylsulphonyl group having a substituent R¹⁰ atthe 4-position of the piperazinyl group wherein said piperazinyl groupis optionally substituted with one or two C₁ to C₄ alkyl groups and isoptionally in the form of its 4-N-oxide;

[0065] R⁵ and R⁶ are each independently selected from H and C₁ to C₄alkyl optionally substituted with C₃ to C₅ cycloalkyl or C₁ to C₄alkoxy, or, together with the nitrogen atom to which they are attached,form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group; and

[0066] R¹⁰ is H; C₁ to C₄ alkyl optionally substituted with one or twosubstituents selected from hydroxy, NR⁵R⁶, CONR⁵R⁶, phenyl optionallysubstituted with C₁ to C₄ alkyl or C₁ to C₄ alkoxy; C₃ to C₆ alkenyl;Het⁴;

[0067] with the proviso that when R¹ is C₁ to C₃ alkyl substituted byphenyl then said phenyl group is not substituted by C₁ to C₄ alkoxy; CN;halo; CF₃; OCF₃; or C₁ to C₄ alkyl.

[0068] A further preferred group of compounds of formulae (I), (IA) and(IB) is that wherein, R¹ is C₁ to C₆ alkyl wherein said alkyl may bebranched or straight chain or R¹ is C₃ to C₆ cycloalkyl

[0069] and wherein when R¹ is C₁ to C₃ alkyl said alkyl group issubstituted by; and wherein when R¹ is C₄ to C₆ alkyl or C₃ to C₆cycloalkyl said alkyl or cycloalkyl group is optionally substituted by;

[0070] one or more substituents selected from:

[0071] hydroxy;

[0072] C₁ to C₂ alkoxy;

[0073] C₃ to C₅ cycloalkyl;

[0074] NR⁷R⁸, NR⁷COR¹¹ or COR¹¹ wherein R⁷ and R⁸ are each independentlyselected from H, C₁ to C₄ alkyl or CO₂R⁹ wherein R⁹ and R¹¹ are aspreviously defined herein;

[0075] a Het¹ group which is an N-linked 4-membered N-containingheterocyclic group;

[0076] a Het³ group which is a C-linked 6-membered heterocyclic groupcontaining an O or S heteroatom optionally containing one or moreheteroatoms selected from O, S or N or a Het³ group which is a C-linked6-membered heterocyclic group containing three N heteroatoms;

[0077] or R¹ is a Het⁴ group which is a C-linked 4-membered heterocyclicgroup containing one heteroatom selected from S, O or N or R¹ is a Het⁴group which is a C-linked 6-membered heterocyclic group containing one,two or three heteroatoms selected from S or O

[0078] wherein any of said heterocyclic groups Het¹, Het², Het³ or Het⁴is saturated, partially unsaturated or aromatic and is optionallysubstituted with one or more substituents selected from C₁ to C₄ alkyl,C₁ to C₄ alkoxy, —CO₂R¹¹, —SO₂R¹², —COR¹¹ or NHR¹¹ wherein R¹¹ and R¹²are as defined hereinbefore and/or wherein any of said heterocyclicgroups is benzo-fused;

[0079] or R¹ is phenyl substituted by one or more substituents selectedfrom: CF₃, —OCF₃, —SO₂R¹², —COR¹¹, —CO₂R¹¹ wherein R¹¹ and R¹² are asdefined hereinbefore;

[0080] R² is C₁ to C₆ alkyl;

[0081] R¹³ is OR³;

[0082] R³ is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl,i-butyl or t-butyl alkyl optionally substituted with one or twosubstituents selected from cyclopropyl, cyclobutyl, hydroxy, methoxy,ethoxy, benzyloxy, phenyl, benzyl, furan-3-yl,tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, pyridin-2-yl,pyridin-3-yl or NR⁵R⁶ wherein R⁵ and R⁶ are each independently selectedfrom H and C₁ to C₂ alkyl;

[0083] R⁴ is a piperazin-1-ylsulphonyl group having a substituent, R¹⁰at the 4-position of the piperazinyl group wherein said piperazinylgroup is optionally substituted with one or two C₁ to C₄ alkyl groupsand is optionally in the form of its 4-N-oxide; and

[0084] R¹⁰ is H, C₁ to C₃ alkyl optionally substituted with one or twosubstituents selected from hydroxy, NR⁵R⁶, CONR⁵R⁶ wherein R⁵ and R⁶ areeach independently selected from H, C₁ to C₄ alkyl and C₃ alkenyl.

[0085] Preferred compounds of the present invention include:

[0086]5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-methoxyethyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0087]5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0088]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-methoxyethyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0089]2-(sec-Butyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0090]2-(iso-Butyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0091]2-(Cyclopropylmethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0092]2-(Cyclobutylmethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0093]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0094]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxy-1-methylethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0095]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-(methylamino)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0096]2-(2-Dimethylaminoethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0097]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0098]5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-dimethylaminoethyl-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0099]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0100]2-{2-[Acetyl(methyl)amino]ethyl}-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxypyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0101]2-(1-Acetylazetidin-3-yl)-5-[2-n-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0102]5-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0103]5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0104]3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0105]5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0106]5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0107]5-[2-Benzyloxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0108]5-[2-iso-Butoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0109]3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxypyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0110]5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0111]3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-iso-propoxypyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0112]5-[(S)-2-sec-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0113]5-[(R)-2-sec-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0114]3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-{(pyridin-2-yl)methyl}pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0115]2-sec-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0116]2-Cyclobutylmethyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0117]3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(S)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0118]3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(R)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0119]5-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(S)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0120]5-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(R)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0121]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-hydroxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0122]2-(2-Dimethylaminoethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0123]2-iso-Butyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0124]2-iso-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0125]2-Cyclobutylmethyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0126]5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-(dimethylamino)-2-oxoethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0127]5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-[methyl(methylsulphonyl)amino]ethyl}-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0128]2-Cyclobutylpropylmethyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0129]2-n-Butyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0130]5-[2-n-Butoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0131]2-(2-Ethoxyethyl)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0132]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(3-methoxypropyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0133]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(S)-(2-methoxypropyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0134]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(R)-(2-methoxypropyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0135]2-(S)-sec-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0136]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0137]2-(R)-sec-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0138]2-Cyclobutyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0139]2-Cyclopentyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0140]2-Cyclopentylmethyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0141]2-Cyclohexyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0142]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(2-ethoxyethyl)-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0143]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[(1S)-1-methyl-2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0144]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[(1R)-1-methyl-2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0145]5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(3-methoxy-n-propyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0146]2-Cyclobutyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

[0147]5-[2-n-Butoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone,

[0148]3-Ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[(1S)-1-methylpropyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone,

[0149]3-Ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[(1R)-1-methylpropyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone,

[0150]2-n-Butyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone,

[0151]2-Cyclopropylmethyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone,

[0152]2-Cyclobutylmethyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(tetrahydro-2-furanylmethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone,

[0153]3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(2-methoxyethoxy)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone,

[0154]5-[2-Ethoxy-5-(4-iso-propylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinoneand

[0155]5-[2-Ethoxy-5-(4-n-propylpiperazin-1-ylsulphonyl)pyridin-3-yl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone.

[0156] A yet further preferred group of compounds of formulae (I), (IA)or (IB) is that wherein

[0157] R¹ is —(CH₂)_(n)(C₃-C₆)cycloalkyl wherein n is 0, 1, 2 or 3; or

[0158] R¹ is methyl, ethyl, iso-propyl or n-propyl substituted by one ormore C₁ to C₄ alkoxy substituents wherein said alkoxy substituent may bedirectly attached to any C-atom within the ethyl, iso-propyl or n-propylgroups other than the C-atom directly linked to the pyrazole ring; or

[0159] R¹ is a C₄ alkyl group selected from i-, n-, sec- or t-butyloptionally substituted by one or more substituents selected from C₁ toC₄ alkoxy or C₃ to C₄ cycloalkyl;

[0160] R² is C₁ to C₄ alkyl;

[0161] R¹³ is OR³ wherein R³ is C₁ to C₄ alkyl optionally substitutedwith one or two C₁ to C₄ alkoxy substituents wherein said C₁ to C₄ alkyland C₁ to C₄ alkoxy groups may optionally be terminated by a haloalkylgroup such as CF₃;

[0162] R⁴ is a piperazin-1-ylsulphonyl group having a singlesubstituent, R¹⁰ at the 4-position of the piperazinyl group and isoptionally in the form of its 4-N-oxide;

[0163] and R¹⁰ is methyl, ethyl, n-propyl or i-propyl.

[0164] A particularly preferred group of compounds of formulae (I), (IA)or (IB) is that wherein

[0165] R¹ is —(CH₂)_(n)(C₃-C₄)cycloalkyl wherein n is 1 or 2; or

[0166] R¹ is —(CH₂)_(n)(C₃-C₆)cycloalkyl wherein n is 0; or

[0167] R¹ is -cyclopentyl methyl; or

[0168] R¹ is methyl, ethyl, i-propyl or n-propyl substituted by methoxy,ethoxy, n-propoxy or i-propoxy wherein said alkoxy substituent may bedirectly attached to any C-atom within the ethyl, iso-propyl or n-propylgroups other than the C-atom directly linked to the pyrazole ring; or

[0169] R¹ is i-, n-, sec- or t-butyl;

[0170] R² is C₂ to C₄ alkyl;

[0171] R¹³ is OR³ wherein the R³ alkyl group is methyl, ethyl, n-propyl,i-propyl, i-butyl, n-butyl, sec-butyl or t-butyl optionally substitutedwith one or two methoxy, ethoxy, n-propoxy or i-propoxy substituents;and R⁴ is a 4-methyl, 4-ethyl, 4-n-propyl or4-1-propylpiperazin-1-ylsulphonyl group.

[0172] In highly preferred embodiment of the present invention there isprovided a compound of the formula (IB) wherein

[0173] R¹ is —(CH₂)_(n)(C₃-C₄)cycloalkyl wherein n is 1 or 2; or

[0174] R¹ is —(CH₂)_(n)(C₃-C₅)cycloalkyl wherein n is 0; or

[0175] R¹ is -cyclopentylmethyl; or

[0176] R¹ is methyl, ethyl, i-propyl or n-propyl substituted by methoxy,ethoxy, n-propoxy or i-propoxy wherein said alkoxy substituent may bedirectly attached to any C-atom within the ethyl, iso-propyl or n-propylgroups other than the C-atom directly linked to the pyrazole ring; or

[0177] R¹ is i-, n-, sec- or t-butyl;

[0178] R² is C₂ to C₄ alkyl; R¹³ is OR³ wherein the R³ alkyl group ismethyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl ort-butyl; and R⁴ is a 4-methyl or 4-ethylpiperazin-1-ylsulphonyl group.

[0179] Highly preferred compounds according to the present inventioninclude:1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazineand salts and polymorphs thereof. Preferred salts of1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazineare sulphonic acid salts, more preferably the p-toluenesulfonate,benzenesulfonate, camphorsulfonate and ethanesulfonate saltsrespectively, and especially the benzenesulfonate.

[0180] According to a further aspect of the present invention there areprovided compounds of the general formula (I):

[0181] or a pharmaceutically or veterinarily acceptable salt thereof, ora pharmaceutically or veterinarily acceptable solvate of either entity,wherein

[0182] R¹ is C₁ to C₆ alkyl or C₃ to C₆ alkenyl, C₃ to C₆ cycloalkyl orC₃ to C₆ cycloalkenyl wherein said alkyl group may be branched orstraight chain and wherein

[0183] when R¹ is C₁ to C₃ alkyl said alkyl group is substituted by; andwherein when R¹ is C₄ to C₆ alkyl, C₃ to C₆ alkenyl or C₃ to C₆cycloalkyl said alkyl, alkenyl or cycloalkyl group is optionallysubstituted by; one or more substituents selected from: hydroxy; C₁ toC₄ alkoxy; C₃ to C₆ cycloalkyl; phenyl substituted with one or moresubstitutents selected from C₁ to C₃ alkyl, C₁ to C₄ alkoxy, C₁ to C₄haloalkyl or C₁ to C₄ haloalkoxy wherein said haloalkyl and haloalkoxygroups contain one or more halo atoms, halo, CN, NO₂, NHR¹¹, NHSO₂R¹²,SO₂R², SO₂NHR¹¹, COR¹¹, CO₂R¹¹ wherein R¹¹ is H, C₁ to C₄ alkyl, C₂ toC₄ alkenyl, C₁ to C₄ alkanoyl, C₁ to C₄ haloalkyl or C₁ to C₄ haloalkoxyand wherein R¹² is C₁ to C₄ alkyl, C₂ to C₄ alkenyl, C₁ to C₄ alkanoyl,C₁ to C₄ haloalkyl or C₁ to C₄ haloalkoxy; NR⁷R⁸, CONR⁷R⁸ or NR⁷COR¹¹wherein R⁷ and R⁸ are each independently selected from H, C₁ to C₄alkyl, C₂ to C₄ alkenyl, C₁ to C₄ alkoxy, CO₂R⁹, SO₂R⁹ wherein saidalkyl, alkenyl or alkoxy groups are optionally substituted by C₁ to C₄haloalkyl or C₁ to C₄ haloalkoxy and wherein R⁹ is C₁ to C₄ alkyl whichis optionally substituted with phenyl wherein said phenyl group isoptionally substituted by one or more substituents selected from C₁ toC₄ alkyl optionally substituted by C₁ to C₄ haloalkyl or C₁ to C₄haloalkoxy, C₁ to C₄ alkoxy, halo, CN, NO₂, NHR¹¹, NHSO₂R¹², SO₂R¹²,SO₂NHR¹¹, COR¹¹ or CO₂R¹¹; Het¹; Het² or Het³; or R¹ is Het⁴ or phenylwherein said phenyl group is optionally substituted by one or moresubstituents selected from C₁ to C₄ alkyl, C₂ to C₄ alkenyl, C₁ to C₄alkoxy, halo, CN, CF₃, OCF₃, NO₂, NHR¹¹, NHSO₂R¹², SO₂R¹², SO₂NHR¹¹,COR¹¹, CO₂R¹¹;

[0184] R² is C₁ to C₆ alkyl, C₃ to C₆ alkenyl or (CH₂)_(n)(C₃ to C₆cycloalkyl) wherein n is 0, 1 or 2;

[0185] R¹³ is OR³ or NR⁵R⁶;

[0186] R³ is C₁ to C₆ alkyl optionally substituted with one or twosubstituents selected from C₃ to C₅ cycloalkyl, hydroxy, C₁ to C₄alkoxy, benzyloxy, NR⁵R⁶, phenyl, Het¹, Het², Het³ or Het⁴ wherein theC₁ to C₆ alkyl and C₁ to C₄ alkoxy groups may optionally be terminatedby a haloalkyl group such as CF₃; C₃ to C₆ cycloalkyl; Het¹, Het², Het³or Het⁴;

[0187] R⁴ is a piperazin-1-ylsulphonyl group having a substituent, R¹⁰at the 4-position of the piperazinyl group wherein said piperazinylgroup is optionally substituted with one or two C₁ to C₄ alkyl groupsand is optionally in the form of its 4-N-oxide;

[0188] R⁵ and R⁶ are each independently selected from H and C₁ to C₄alkyl optionally substituted with C₃ to C₅ cycloalkyl or C₁ to C₄alkoxy, or, together with the nitrogen atom to which they are attached,form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group;

[0189] R¹⁰ is H; C₁ to C₄ alkyl optionally substituted with one or twosubstituents selected from hydroxy, NR⁵R⁶, CONR⁵R⁶, phenyl optionallysubstituted with C₁ to C₄ alkyl or C₁ to C₄ alkoxy; C₂ to C₆ alkenyl orHet⁴;

[0190] Het¹ is an N-linked 4-, 5- or 6-membered nitrogen-containingheterocyclic group optionally containing one or more further heteroatomsselected from S, N or O;

[0191] Het² is a C-linked 5-membered heterocyclic group containing an O,S or N heteroatom optionally containing one or more heteroatoms selectedfrom O or S;

[0192] Het³ is a C-linked 6-membered heterocyclic group containing an Oor S heteroatom optionally containing one or more heteroatoms selectedfrom O, S or N or Het³ is a C-linked 6-membered heterocyclic groupcontaining three N heteroatoms;

[0193] Het⁴ is a C-linked 4-, 5- or 6-membered heterocyclic groupcontaining one, two or three heteroatoms selected from S, O or N; and

[0194] wherein any of said heterocyclic groups Het¹, Het², Het³ or Het⁴may be saturated, partially unsaturated or aromatic and wherein any ofsaid heterocyclic groups may be optionally substituted with one or moresubstituents selected from C₁ to C₄ alkyl, C₂ to C₄ alkenyl, C₁ to C₄alkoxy, halo, CO₂R¹¹, COR¹¹, SO₂R¹² or NHR¹¹ and/or wherein any of saidheterocyclic groups is benzo-fused;

[0195] with the provisos that (a) when R¹ is C₁ to C₃ then Het¹ is notmorpholinyl or piperidinyl and (b) when R¹ is C₁ to C₃ substituted byphenyl then said phenyl group is not substituted by C₁ to C₄ alkoxy,halo, CN, CF₃, OCF₃ or C₁ to C₄ alkyl.

[0196] In a further aspect, the present invention provides processes forthe preparation of compounds of formulae (I), (IA) and (IB), theirpharmaceutically and veterinarily acceptable salts, and pharmaceuticallyand veterinarily acceptable solvates of either entity, as illustratedbelow. It will be appreciated by persons skilled in the art that, withincertain of the processes described, the order of the synthetic stepsemployed may be varied and will depend inter alia on factors such as thenature of other functional groups present in a particular substrate, theavailability of key intermediates and the protecting group strategy (ifany) to be adopted. Clearly, such factors will also influence the choiceof reagent for use in the said synthetic steps. Illustrative of aprotecting group strategy is the route to the azetidine analogues(Examples 18, 19 and 20), the precursor to which (preparations 63, 66and 61 respectively) contain t-butoxycarbonyl (Boc) as the nitrogenprotecting group.

[0197] It will also be appreciated that various standard substituent orfunctional group interconversions and transformations within certaincompounds of formulae (I), (IA) or (IB) will provide other compounds offormulae (I), (IA) or (IB). Examples include alkoxide exchange at the2-position of the 5-(pyridin-3-yl) substituent (see conversions ofExample 3 to Examples 27, Example 8 to Example 28 and 29, Example 21 toExample 32 and 33, Example 4 to Examples 41, Example 9 to Example 43,and Example 66 to Example 75), amine exchange at the 2-position of the5-(pyridin-3-yl) substituent (see conversions of Example 7 to Examples78), reactions at a nitrogen containing substituent, such as reductivealkylation (Example 18 to Example 21), acetamide formation (Examples 18,and 20 to Examples 22 and 24 respectively) or sulphonamide formation(Preparations 68, 67 to Examples 25 to 62 respectively), and reductionof a nitro functionality to provide an amino group (Example 63 toExample 64). The deprotection and transformations described herein andas illustrated in the Examples and Preparations sections may be effectedin a “one-pot” procedure (see for example the conversion of the compoundof preparation 65 into the compound of example 26).

[0198] The following processes are illustrative of the general syntheticprocedures which may be adopted in order to obtain the compounds of theinvention.

[0199] 1. A compound of formula (I):

[0200] wherein formula (I) may equally be represented by generalformulae (IA) and (IB) and wherein R¹, R², R⁴ and R¹³ are as previouslydefined herein may be prepared from a compound of general formula (IX):

[0201] wherein R^(P) is R¹³ (i.e. OR³ or NR⁵R⁶) or X wherein R¹³, R³, R⁵and R⁶ are as defined hereinbefore and X is a leaving group and whereingeneral formula (IX) can be represented by formulae (IXA), (IXB) or(IXC) respectively:

[0202] wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously definedherein and wherein X is a leaving group and may be any group which isdisplaceable by an amino group of the formula —NR⁵R⁶ or by an alkoxygroup and wherein the intermediate compounds of general formulae (IXA)and (IXB) can be represented by their regioisomeric general formulae aspreviously illustrated for compounds having the general formulae (1).Suitable leaving groups, X, for use herein include halogen, alkoxy,amino, tosylate groups and further groups are detailed hereinafter.

[0203] 1.1 A compound of formula (I) wherein R¹³═NR⁵R⁶ may be preparedby cyclisation of a compound of general formula (IXA):

[0204] wherein R¹, R², R⁴, R⁵ and R⁶ are as previously defined hereinfor compounds of the formula (I), (IA) or (IB). Preferably, thecyclisation is base-mediated, using an alkali metal salt of a stericallyhindered alcohol or amine. For example, the required cyclisation may beeffected using about a 1- to 5-, preferably a 1.2- to 3.5-fold excess ofpotassium t-butoxide, potassium bis(trimethylsilyl)amide or cesiumcarbonate, optionally in the presence of molecular sieves, in a suitablesolvent, such as for example an inert solvent e.g. DMF or NHR⁵R⁶ ormixtures thereof, at the reflux temperature of the reaction mixtureoptionally in the presence of about a 1 molar equivalent of ethylacetate or ethyl pivalate, or, the reaction can optionally be carriedout in a sealed vessel at about 100-130° C. optionally in the presenceof about a 1 molar equivalent of ethyl acetate or ethyl pivalate.

[0205] 1.2 A general route for the synthesis of compounds (I) viacompounds (IXB) is illustrated in Scheme 1 wherein said intermediatecompounds (IXB) have the general formula:

[0206] wherein R¹, R² and R⁴ are as previously defined herein forcompounds of the formula (I), (IA) and (IB) and wherein X is a leavinggroup as defined hereinbefore, by reaction in the presence of ⁻OR³ and ahydroxide trapping agent. The conversion (IXB) to (I) can be undertakenin either a stepwise process or a one-pot process. A number of stepwisepermutations are feasible, some of which are subsets of others. Theseinclude

[0207] i) cyclisation (IXB to XXX) followed by displacement (XXX to I);

[0208] ii) cyclisation (IXCa to XXX) followed by displacement (XXX toI);

[0209] iii) displacement (IXB to IXC) followed by cyclisation (IXC toI); and

[0210] iv) displacement (IXCa to IXC) followed by cyclisation (IXC to I)wherein compounds (XXX) and (IXCa) have the general formulae:

[0211] wherein R¹, R², R⁴ and X are as defined herein before and OR^(3a)is an alkoxy group which is different from and displaceable by thedesired OR³ group on the final compounds of general formula (I) andwherein R^(3a) is selected from C₁ to C₆ alkyl optionally substitutedwith one or two substituents selected from C₃ to C₅ cycloalkyl, hydroxy,C₁ to C₄ alkoxy, benzyloxy, NR⁵R⁶, phenyl, Het¹, Het², Het³ or Het⁴wherein the C₁ to C₆ alkyl and C₁ to C₄ alkoxy groups may optionally beterminated by a haloalkyl group such as CF₃ and wherein the C₃-C₅cycloalkyl group may optionally be substituted by C₁-C₄ alkyl, hydroxyor halo; C₃ to C₆ cycloalkyl; Het¹, Het², Het³ or Het⁴. PreferablyR^(3a)is C₁ to C₆ alkyl.

[0212] To effect initial displacement without significant simultaneouscyclisation it is preferred that the displacement with ⁻OR³ (in (iii) or(iv)) is carried out in the range of from about 80° C. to about 90° C.to provide a compound of the general formula (IXC). Subsequentcyclisation to a compound of general formula (I) is generally carriedout at a temperature greater than about 115° C.

[0213] To effect initial cyclisation without significant simultaneousdisplacement it is preferred that, for (IXCa) to (XXX) (in (ii)), thereaction is conducted at a temperature greater than about 110° C. with⁻OR^(3a) in R^(3a)OH. Subsequent displacement to a compound of generalformula (I) is generally carried out with ⁻OR³ in R³OH in the range offrom about 80° C. to about 90° C.

[0214] For conversion of (IXB) to (I) (ie. (i) above), it may bepreferred to obtain compounds of general formula (I) directly fromcompounds of general formula (IXB) since both the cyclisation anddisplacement components of this reaction can be carried out in a“one-pot” reaction. Such a “one-pot” process can be run at lowerpressures (ie. nearer ambient pressure) than say a stepwise cyclisationand displacement process (ie. (ii) above) if the boiling point of R³OHis higher than that of R^(3a)OH and where the ambient boiling point ofR^(3a)OH is less than about 115° C. (ie. too low to effect cyclisationat ambient pressure). It should be noted that is may still be necessaryto operate such processes at higher temperatures than the boiling pointof HOR³, i.e. at higher pressure.

[0215] In the case of compounds of general formula (IXC) as detailedhereinafter wherein X is OR³, compounds of general formula (I) can beobtained by direct cyclisation by reacting in the presence of anauxiliary base, a hydroxide trapping agent and an appropriate solventR³OH or an inert solvent or a combination thereof.

[0216] The temperature of the reaction of compounds of the generalformula (IXB) to compounds of the general formula (I) (such as thecorresponding formation of compounds (IA) and (IB)) is preferably atleast about 80° C., more preferably about 80 to about 130° C., morepreferably still about 100 to about 130 C and most preferably about 115to about 125° C. These temperatures are also applicable for theconversion of compounds (XXX) to (I), although the temperature in thiscase could also probably be lower (e.g. about 60° C.) since there is nocyclisation taking place.

[0217] Preferably compounds of formula (I), or (IA), or (IB) wherein

[0218] R¹ is —(CH₂)_(n)(C₃-C₄)cycloalkyl wherein n is 1 or 2; or

[0219] R¹ is —(CH₂)_(n)(C₃-C₆)cycloalkyl wherein n is 0; or

[0220] R¹ is -cyclopentylmethyl; or

[0221] R¹ is methyl, ethyl, i-propyl or n-propyl substituted by methoxy,ethoxy, n-propoxy or i-propoxy wherein said alkoxy substituent may bedirectly attached to any C-atom within the ethyl, iso-propyl or n-propylgroups other than the C-atom directly linked to the pyrazole ring; or

[0222] R¹ is i-, n-, sec- or t-butyl;

[0223] R² is C₂ to C₄ alkyl; R¹³ is OR³ wherein the R³ alkyl group ismethyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl ort-butyl optionally substituted with one or two methoxy, ethoxy,n-propoxy or i-propoxy substituents; and R⁴ is a 4-methyl, 4-ethyl,4-n-propyl or 4-1-propylpiperazin-1-ylsulphonyl group are prepared fromcompounds of general formula (IXB) wherein X is OR³ (i.e. compounds ofgeneral formula (IXC) as detailed hereinbefore and after).

[0224] Thus, according to a further aspect of the present inventionthere is provided a further process for the preparation of a compound ofgeneral formula (I):

[0225] or a compound of general formula (IA), or (IB) wherein

[0226] R¹ is —(CH₂)_(n)(C₃-C₄)cycloalkyl wherein n is 1 or 2; or

[0227] R¹ is —(CH₂)_(n)(C₃-C₆)cycloalkyl wherein n is 0; or

[0228] R¹ is -cyclopentylmethyl; or

[0229] R¹ is methyl, ethyl, i-propyl or n-propyl substituted by methoxy,ethoxy, n-propoxy or i-propoxy wherein said alkoxy substituent may bedirectly attached to any C-atom within the ethyl, iso-propyl or n-propylgroups other than the C-atom directly linked to the pyrazole ring; or

[0230] R¹ is i-, n-, sec- or t-butyl;

[0231] R² is C₂ to C₄ alkyl; R¹³ is OR³ wherein the R³ alkyl group ismethyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl ort-butyl optionally substituted with one or two methoxy, ethoxy,n-propoxy or i-propoxy substituents; and R⁴ is a 4-methyl, 4-ethyl,4-n-propyl or 4-1-propylpiperazin-1-ylsulphonyl group comprisingreacting a compounds of general formula (IXC):

[0232] wherein R1, R², R³ and R⁴ are as defined previously herein,wherein said reaction is carried out in the presence of —OR³ and ahydroxide trapping agent, or alternatively reacting in the presence ofhydroxide trapping agent and an auxiliary base.

[0233] Intermediates of the general formula (IXC) and more specifically(IXCA) and (IXCB) form further aspects of the invention.

[0234] A particular advantage of the use of the hydroxide trapping agentis that a higher yield of final product (compounds of general formula(I), (IA) or (IB)) can be obtained than for the same reaction where thetrapping agent is not present.

[0235] Preferably the hydroxide trapping agent is an ester. Morepreferably said hydroxide trapping agent is an ester of the formula:

[0236] wherein OT is OR³ or the residue of a bulky alcohol or anon-nucleophilic alcohol or TOH is an alcohol which can beazeotropically removed during the reaction; and C(O)V is the residue ofa carboxylic acid. For example, where OR³ is OEt in compound (IXC) thehydroxide trapping agent (TOC(O)V) could be e.g. ethyl acetate or ethylpivalate. Preferably V is a C₁ to C₄ alkyl group.

[0237] Preferably X is selected from the group consisting of —OR³, halo,optionally substituted arylsulphonyloxy, preferably phenylsulphonyloxy,more preferably a para-substituted aryl (phenyl) such as by a C₁-C₄alkyl group e.g. p-toluenesulphonyloxy; C₁-C₄ alkylsulphonyloxy e.g.methanesulphonyloxy; nitro or halo substituted benzenesulphonyloxypreferably para-substituted e.g. p-bromobenzenesulfonyloxy orp-nitrobenzenesulphonyloxy; C₁-C₄ perfluoroalkylsulphonyloxy e.g.trifluoromethylsulphonyloxy; optionally substituted aroyloxy such asbenzoyloxy; C₁-C₄ perfluoroalkanoyloxy such as trifluoroacetyloxy; C₁-C₄alkanoyloxy such as acetyloxy; diazonium; quatenaryammonium C₁-C₄alkylsulphonyloxy; halosulphonyloxy e.g. fluorosulphonyloxy and otherfluorinated leaving groups; and diarylsulphonylamino e.g. ditosyl(NTs₂).

[0238] More preferably, X is a C₁-C₆ primary or secondary alkoxy and isespecially a C₁-C₄ alkoxy group such as ethoxy or methoxy.

[0239]⁻OR³ can act both as a nucleophile (to displace the leaving groupby nucleophilic substitution) and as a base (to bring about thecyclisation).

[0240]⁻OR³ can be generated in solution from, for example, a salt ZOR³(wherein Z is a cation) such as a metal salt. More particularly analkali (such as sodium or potassium) or alkaline earth metal salt of—OR³ in a suitable solvent would give rise to —OR³ in solution. Inanother embodiment, —OR³ is formed in situ from R³OH plus an auxiliarybase (i.e. a base other than —OR³). However, in another system, ZOR³could be used in the reaction system with an auxiliary base.

[0241] As will be appreciated the solvent in which the reaction takesplace can be R³OH or an inert solvent (or a mixture of both). By inertsolvent we mean a solvent which will not form a nucleophile under thereaction conditions or if a nucleophile is formed it is sufficientlyhindered or unreactive such that it does not substantially compete inthe displacement reaction. When R³OH is used as a source of —OR³, then aseparate solvent is not essentially required but an (auxiliary) inertsolvent (i.e. a solvent other than R 30H) may be used as a co-solvent inthe reaction.

[0242] Suitable solvents are as follows: R³OH, a secondary or tertiaryC₄-C₁₂ alkanol, a C₃-C₁₂ cycloalkanol, a tertiary C₄-C₁₂ cycloalkanol, asecondary or tertiary (C₃-C₇ cycloalkyl)C₂-C₆ alkanol, a C₃-C₉ alkanone,1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran,1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene,acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide,N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.

[0243] More preferably, the solvent is R³OH, a tertiary C₄-C₁₂ alkanol,a tertiary C₄-C₁₂ cycloalkanol, a tertiary (C₃-C₇ cycloalkyl)C₂-C₆alkanol, a C₃-C₉ alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane,diglyme, tetrahydrofuran, 1,4-dioxan, toluene, xylene, chlorobenzene,1,2-dichlorobenzene, acetonitrile, dimethyl sulphoxide, sulpholane,dimethylformamide, N-methylpyrrolidin-2-one, pyridine, and mixturesthereof.

[0244] Most preferably the solvent is R³OH, which means that ⁻OR 3 isformed in situ, such as in the presence of an auxiliary base.

[0245] A wide range of auxiliary bases can be used in the process of theinvention. Typically the bases would not substantially compete with —OR³in the nucleophilic substitution of X (i.e. they would be nonnucleophilic) such as by suitably being sterically hindered.

[0246] Preferably the auxiliary base is selected from the groupconsisting of a sterically hindered-base, a metal-hydride, metal oxide,metal carbonate and metal bicarbonate.

[0247] The sterically hindered base is advantageously a metal salt of asterically hindered alcohol or amine.

[0248] More preferably the auxiliary bases in accordance with theinvention are selected from the group consisting of metal salts of asterically hindered alcohol or amine such as a secondary or tertiaryC₄-C₁₂ alkanol, a C₃-C₁₂ cycloalkanol and a secondary or tertiary (C₃-C₈cycloalkyl)C₁-C₆ alkanol, a N-(secondary or tertiary C₃-C₆alkyl)-N-(primary, secondary or tertiary C₃-C₆ alkyl)amine, a N-(C₃-C₈cycloalkyl)-N-(primary, secondary or tertiary C₃-C₆ alkyl)amine, adi(C₃-C₈ cycloalkyl)amine or hexamethyldisilazane;1,5-diazabicyclo[4,3,0]non-5-ene and 1,8-diazabicyclo[5,4,0]undec-7-ene;a metal hydride, oxide, carbonate, and bicarbonate.

[0249] Yet more preferably the auxiliary bases in accordance with theinvention are selected from the group consisting of metal salts of asterically hindered alcohol or amine such as a tertiary C₄-C₁₂ alkanol,a C₃-C₁₂ cycloalkanol and a tertiary (C₃-C₈ cycloalkyl)C₁-C₆ alkanol, aN-(secondary or tertiary C₃-C₆ alkyl)-N-(primary, secondary or tertiaryC₃-C₆ alkyl)amine, a N-(C₃-C₈ cycloalkyl)-N-(primary, secondary ortertiary C₃-C₆ alkyl)amine, a di(C₃-C₈ cycloalkyl)amine orhexamethyldisilazane; 1,5-diazabicyclo[4,3,0]non-5-ene and1,8-diazabicyclo[5,4,0]undec-7-ene; a metal hydride, oxide, carbonate,and bicarbonate.

[0250] More preferably still, the auxiliary base is selected from thesterically hindered bases of the previous paragraph (i.e. all of themexcept the metal hydride, oxide, carbonate and bicarbonate).

[0251] Most preferably still, the auxiliary base is the metal salt of atertiary C₄-C₆ alcohol such as the alkali or alkaline earth metal salts(e.g. Na/K) of t-butanol or t-amyl alcohol, or the base is KHMDS.

[0252] Most preferably, the auxiliary base is the alkali metal salt oft-butanol (e.g. potassium t-butoxide).

[0253] The metal of the salt of ZOR³ and the auxiliary base can beindependently selected from alkali metals (lithium, sodium, potassium,rubidium, cesium) or alkaline earth metals (beryllium, magnesium,calcium, strontium, barium). Preferably the metal is sodium, potassium,lithium or magnesium. More preferably the metal is sodium or potassium.

[0254] To maximise yields, it is further preferred that when X is anygroup hereinbefore defined except —OR³, then at least about 1 molecularequivalent of auxiliary base and —OR³ are used. If —OR³ also functionsas a base (i.e. there is no auxiliary base present) then preferably atleast about 2 equivalents of ⁻OR³ are present. Suitably, at least about1 equivalent of trapping agent (preferably at least about 2 equivalents)is present. In the case where X═OR³ (i.e. starting from (IXC) ratherthan (IXB) then, in theory, at least 1 equivalent of base is required,wherein said base may be —OR3 or auxiliary base.

[0255] The temperature of the reaction of compounds of the generalformula (IXC) to compounds of the general formula (I) (such as thecorresponding formation of compounds (IA) and (IB)) is preferably atleast about 80° C., more preferably about 80 to about 130° C., morepreferably still about 100 to about 130° C. and most preferably about115 to about 125° C.

[0256] The reaction temperature attainable to effect the conversion ofcompounds of the general formulae (IXB), (IXC) or (XXX) to compounds ofthe general formula (I) depends on the solvent, the nature of ⁻OR³ andX. When X is OR^(3a) (wherein OR^(3a) and OR³ are not the same), i.e. acompound of the formula (IXC^(a)) and R³OH is the solvent, preferably XH(such as C₁-C₆ alkohol) is removed azeotropically (of course thereaction vessel must be configured to distill over the azeotropemixture) with R³OH by running the reaction at the azeotrope temperatureof XH and. R³OH. In this way the yield and quality of the final productcan be further improved. For example, (where X is an alkoxy, preferablyethanol) the conversion of compound (XXX), (IXB) or (IXC) to (I) ispreferably carried out at the azeotrope temperature of the alcohol (i.e.XH (preferably ethanol)) with R³OH. When X═OR³ and the solvent is R³OHthere is no requirement to azeotrope out R³OH.

[0257] Thus in a preferred embodiment of the present invention there isprovided a process for the synthesis of compounds of general formula(I), (IA) or (IB) and in particular compounds of general formula (I),(IA) or (IB) wherein R¹ is —(CH₂)_(n)(C₃-C₄)cycloalkyl wherein n is 1 or2; or R¹ is —(CH₂)_(n)(C₃-C₆)cycloalkyl wherein n is 0; or R¹ is—(CH₂)_(n)(C₅)cycloalkyl wherein n is 1; or R¹ is methyl, ethyl,i-propyl or n-propyl substituted by methoxy, ethoxy, n-propoxy ori-propoxy wherein said alkoxy substituent may be directly attached toany C-atom within the ethyl, iso-propyl or n-propyl groups; or R¹ is i-,n-, sec- or t-butyl; R² is C₂ to C₄ alkyl; R¹³ is OR³ wherein the R³alkyl group is methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl,sec-butyl or t-butyl optionally substituted with one or two methoxy,ethoxy, n-propoxy or i-propoxy substituents; and R⁴ is a 4-methyl,4-ethyl, 4-n-propyl or 4-1-propylpiperazin-1-ylsulphonyl group whereinsaid process comprises reacting a compound of general formula (XIB),(XIC) or (XID) respectively:

[0258] a) with R³OH and auxiliary base, optionally in an inert solventand in the presence of said trapping agent; or

[0259] b) with ZOR³ and an auxiliary base in R³OH or an inert solvent orboth, in the presence of said trapping agent; or

[0260] c) with ZOR³ and R³OH or an inert solvent or both, in thepresence of said trapping agent; or

[0261] d) with auxiliary base, inert solvent or R³OH or a combinationthereof and a hydroxide trapping agent for compounds of the generalformula (IXC).

[0262] 1.3 For compounds of the general formula (IXB) wherein X is OR³and an alcohol is selected as solvent a compound of formula (I) may beprepared by cyclisation of a compound of general formula (IXC):

[0263] wherein R¹, R², R³ and R⁴ are as previously defined herein forcompounds of the formula (I), (IA) and (IB). In said reaction theappropriate alcohol of formula R³OH should be employed as the solvent inorder to obviate potential problems associated with alkoxide exchange atthe 2-position of the pyridine ring or an inert solvent or a mixture ofthe two. The appropriate alcohol as defined herein means that thesolvent alcohol should be of the same alkyl chain length as the alkoxy(—OR³) substituent, for example, where —OR³ is ethoxy, ethanol is theappropriate alcohol. Preferably, said cyclisation is base-mediated,using an alkali metal salt of a sterically hindered alcohol or amine.For example, the required cyclisation may be effected using about a 1-to 8, preferably about a 1- to 5-, more preferably a 1.2- to 3.5-foldexcess of potassium t-butoxide or potassium bis(trimethylsilyl)amide,optionally under suitable drying conditions i.e. in the presence ofmolecular sieves or under azeotroping conditions, in a suitable solventas described above at the reflux temperature of the reaction mixtureoptionally in the presence of about 1 to 2 molar equivalents of ahydroxide trapping agent such as ethyl acetate or ethyl pivalate, or,the reaction can optionally be carried out in a sealed vessel at about100-130° C. optionally in the presence of about 1 to 2 molar equivalentsof a hydroxide trapping agent such as ethyl acetate or ethyl pivalate.

[0264] Alternative reaction conditions for the cyclisation reactions ofcompounds of (IXC) wherein X is OR are to conduct the reaction withabout 1.2 to 4.5 molecular equivalents of sterically hindered base suchas potassium t-butoxide or KHMDS, optionally in a sealed vessel at fromabout 100° C. to about 150° C. with, rather than an alcohol of formulaR³OH as solvent, a sterically hindered alcohol, e.g.3-methylpentan-3-ol, as solvent optionally in the presence of about 1 or2 molar equivalents of ethyl acetate or ethyl pivalate.

[0265] A compound of formula (IXA) or a compound of general (IXB)wherein X is OR³ (i.e. a compound of general formula (IXC)) may beprepared by a coupling reaction between a compound of formula (VII):

[0266] wherein R¹ and R² are as previously defined for formulae (IXA),(IXB) or (IXC) with a compound of formula (XA), (XB) or (XC)respectively:

[0267] wherein R³, R⁴, R⁵, R⁶ and X are also as previously defined forformulae (IXA), (IXB) or (IXC). Where either R⁵ and/or R⁶ in the —NR⁵R⁶group of formula (XA) are H, then a suitable N-protecting group strategymay be advantageously employed. Any known suitable protecting groupstrategy may be used.

[0268] The coupling reaction may be carried out using conventional amidebond-forming techniques, e.g. via the acyl chloride derivative of (XA)or (XB) in the presence of up to about a five-fold excess of a tertiaryamine such as triethylamine or pyridine to act as scavenger for the acidby-product (HY), optionally in the presence of a catalyst such as4-dimethylaminopyridine, in a suitable solvent such as dichloromethane,at from about 0° C. to about room temperature. For convenience pyridinemay also be used as the solvent.

[0269] In particular, any one of a host of amino acid couplingvariations may be used. For example, the acid of formula (XA), (XB) or(XC) or a suitable salt (e.g. sodium salt) thereof may be activatedusing a carbodiimide such as 1,3-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminoprop-1-yl)carbodiimide optionally in thepresence of 1-hydroxybenzotriazole hydrate and/or a catalyst such as4-dimethylaminopyridine, or by using a halotrisaminophosphonium saltsuch as bromotris(pyrrolidino)phosphonium hexafluorophosphate or byusing a suitable pyridinium salt such as 2-chloro-1-methylpyridiniumiodide. Either type of coupling is conducted in a suitable solvent suchas dichloromethane, tetrahydrofuran or N,N-dimethylformamide, optionallyin the presence of a tertiary amine such as triethylamine orN-ethyldiisopropylamine (for example when either the compound of formula(VII), or the activating reagent, is presented in the form of an acidaddition salt), at from about 0° C. to about room temperature.Preferably, from 1 to 2 molecular equivalents of the activating reagentand from 1 to 3 molecular equivalents of any tertiary amine present areemployed.

[0270] In a further variation, the carboxylic acid function of (XA),(XB) or (XC) may first of all be activated using up to about a 5% excessof a reagent such as N,N-carbonyldiimidazole in a suitable solvent, e.g.ethyl acetate or butan-2-one, at from about room temperature to about80° C., followed by reaction of the intermediate imidazolide with (VII)at from about 20° C. to about 90° C.

[0271] It will be appreciated that the general formula (VII) can also berepresented by the regioisomeric formulae (VIIA) and (VIIB):

[0272] wherein R¹ and R² are as previously defined herein.

[0273] The 4-aminopyrazole-5-carboxamide compounds having the generalformulae (VII), (VIIA) or (VIIB) may be prepared from pyrazole compoundsof the general formula (XIII):

[0274] wherein R^(q) is selected from OH, C₁-C₆ alkoxy or NR⁵R⁶ whereinR⁵ and R⁶ are as hereinbefore defined, according to the proceduresdetailed in the preparations section herein and as particularlydescribed in Preparations 96(a) to (h).

[0275] Compounds having the general formulae (XA) or (XC) may beprepared from the carboxylic acid compounds of the general formulae(VIIIA), (VIIIB) or (VIIIC) respectively:

[0276] wherein R³, R⁵ and R⁶ are as defined for compounds of the generalformulae (I), (IA) and (IB) by reaction with a 4-R¹⁰-piperizinylcompound, such as for example 4-methylpiperizine. Such reaction can beconducted at from about 0° C. to about room temperature, preferably inthe presence of an appropriate solvent such as a C₁ to C₃ alkanol ordichloromethane optionally in the presence of a suitable base such astriethylamine to scavenge the acid by-product (HY). Where either R⁵ orR⁶ is H a suitable amino protecting group strategy may be employed asdetailed hereinbefore.

[0277] Compounds of the general formulae (VIIIA), (VIIIB) or (VIIIC) maybe prepared from compounds of the general formulae (XIA), (XIB) or (XIC)respectively:

[0278] wherein R³, R⁵, R⁶ and X are as defined for compounds of thegeneral formulae (I), (IA) and (IB) by the application of known methodsfor converting amino to an SO₂Y group, wherein Y is halo, preferablychloro. For example, when Y is chloro, by the action of about a two-foldexcess of sodium nitrite in a mixture of concentrated hydrochloric acidand glacial acetic acid at from about −25° C. to about 0° C., followedby treatment with excess liquid sulphur dioxide and a solution of abouta three-fold excess of cupric chloride in aqueous acetic acid at fromabout −15° C. to about room temperature. When R¹³ contains a primary orsecondary amino group, protection of the said amino group with an acidstable group such as acetyl or benzyl will generally be advantageous.

[0279] Compounds of the general formula (XIA), (XIB) and (XIC) may beprepared by reduction of compounds of the general formulae (XIIA),(XIIB) and (XIIC) respectively:

[0280] wherein R³, R R⁶ and X are as previously defined. Such conversionof compounds of the general formulae (XIIA), (XIIB) and (XIIC) tocompounds of the general formulae (XIA), (XIB) and (XIC) can be achievedby conventional catalytic or catalytic transfer hydrogenationprocedures. Typically, the hydrogenation is achieved using a Raney (RTM)nickel catalyst or a palladium catalyst such as 10% Pd on charcoal, in asuitable solvent such as ethanol at a hydrogen pressure of from about345 kPa (50 psi) to about 414 kPa (60 psi) at from about roomtemperature to about 60° C., preferably from about 40° C. to about 50°C.

[0281] Intermediates of the general formula (IXC) as described in 1.2and 1.3 hereinbefore can be prepared via a coupling reaction between acompound of the general formula (XB) and a compound of the generalformula (VII) wherein said coupling may be achieved by any of themethods described hereinbefore. Compounds of general formula (XB) may beprepared according to the route outlined in Scheme 2.

[0282] With reference to Scheme 2, the intermediate of formula (XB) isformed from a compound of formula (XIV), the exact process beingdependent on leaving group X.

[0283] For compounds of formula (XB) wherein X=arylsulfonyloxy, C₁-C₄alkylsulfonyloxy, C₁-C₄ perfluoroalkylsulfonyloxy, aryloxy, C₁-C₄perfluoroalkanoyloxy, C₁-C₄ alkanoyloxy, quarternaryammonium C₁-C₄alkylsulfonyloxy or halosulfonyloxy, compound (XB) can be formed fromcompounds (XIV) (wherein Q=OH and W=OH) and an appropriate derivatisingagent, more particularly an appropriate sulphonylating agent such asarylsulfonylhalide, C₁-C₄ alkylsulfonylhalide, C₁-C₄perfluoroalkylsulfonylhalide, arylhalide, C₁-C₄ perfluoroalkanoylhalide,C₁-C₄ alkanoylhalide, quarternary ammonium C₁-C₄ alkylsulfonylhalide orhalosulfonylhalide, or an appropriate arylating agent such asarylhalide, or an appropriate acylating agent such as C₁-C₄perfluoroalkanoylhalide, or C₁-C₄ alkanoylhalide), respectively(preferably the halide substituent of the above is chloride), in anappropriate solvent. Compounds of formula (XIV) (wherein Q=OH and W=OH)can be formed from compounds (XV) (wherein P is hydrolisable group) viause of a hydrolising agent, preferably a hydroxide base (ideally 2 molarequivalents), more preferably a metal hydroxide such as sodiumhydroxide, in an appropriate solvent, such as water. The metal of thehydroxide base can be as defined hereinbefore for Z (in ZOR). This willalso apply for other reactions of scheme 2 and 3 hereafter wherehydroxide base/hydrolising agent is used. Where P is group which is nothydrolisable by hydroxide then a suitable de-protection strategy shouldbe employed according to standard literature practise.

[0284] Compounds of formula (XB) where X=chloro, can be formed from(XIV) wherein Q=Cl and W=P (such as OEt) (i.e. formula XV) and ahydroxide base (ideally 1 molar equivalent), such as sodium hydroxidepreferably in an appropriate solvent, such as water and a deprotectingagent.

[0285] Preferably the deprotecting agent as used herein in accordancewith the invention is a hydrolysing agent, more preferably a hydroxidenucleophile, advantageoulsly a hydroxide base (ideally 1 molarequivalent), such as sodium hydroxide preferably in an appropriatesolvent, such as water.

[0286] Compounds of formula (XB) wherein X=diazonium, can be formed from(XIV) (wherein Q=NH₂, W=OH) and nitrous acid. Compounds of formula (XIV)(wherein Q=NH₂, W=OH) can be formed from compounds of formula (XIV)(wherein Q=NH₂, W=P, e.g. OEt) and a deprotecting agent such as ahydroxide base e.g. sodium hydroxide, in an appropriate solvent, such aswater. Intermediate (XIV) (Q=NH₂ W=P, e.g. OEt) is formed from (XV) andan ammoniating agent, such as ammonia, in an appropriate solvent, suchas water.

[0287] Compounds of formula (XB) wherein X=diarylsulfonylamino, can beformed from (XIV) (wherein Q=NH₂, W=OH) and an appropriate derivatisingagent, preferably an appropriate sulphonylating agent such asarylsulphonylhalide, preferably arysulfonylchloride (ideally at least 2molar equivalents) and preferably in the presence of a base (ideally 2molar equivalents thereof), such as triethylamine in an appropriatesolvent.

[0288] Compounds of formula (XB) wherein X=C₁-C₆ (preferably C₁-C₄)preferably primary or secondary alkoxy, can be formed from (XIV)(wherein Q=C₁-C₆ (preferably C₁-C₄) primary or secondary alkoxy and W=P,such as OEt) and a deprotecting agent (for P=OEt), preferably ahydroxide base, such as sodium hydroxide, in an appropriate solvent,such as water. Compounds of formula (XIV) (wherein Q=C₁-C₆ (preferablyC₁-C₄) primary or secondary alkoxy, W=P e.g. OEt) can be formed from(XV) and an appropriate alkoxide, OR wherein R is C₁-C₆ alkyl morepreferably C₁-C₄ primary or secondary alkyl, such as sodium ethoxide inan appropriate solvent such as toluene. Most preferably P=X (wherein Xis an alkoxy) since this avoids trans-esterification issues.

[0289] The compounds of formula (XV) can be formed from compounds offormula (XVI) by reaction with a mono-N-substituted piperazine groupwherein the mono-substituent R¹⁰ as defined herein before, optionally inthe presence of a supplementary base (which does not react irreversiblywith the sulphonyl chloride moiety) such as triethylamine preferably inan appropriate solvent, such as toluene. “D” in compounds (XV) and (XVI)is Cl or Br. The monosubstituted piperazine group may also be the basewhere more than one equivalent of monosubstituted piperazine is present.Preferably about 2 equivalents are used.

[0290] Where a supplementary base is used it either does not react withthe sulphonyl chloride moiety (such as a metal oxide, carbonate orbicarbonate) or it reacts with the sulphonyl chloride moiety in such away as to keep it activated to nucleophilic attack (e.g. a tertiaryamine such as triethylamine). The amine NH(R3)(R4) may also act as abase, in which case preferably more than one equivalent is present, morepreferably about 2 equivalents (or more).

[0291] The compounds of formula (XVI) can be formed from compounds offormula (XX) in the presence of a chlorinating or brominating agent suchas thionyl chloride or thionyl bromide more preferably in the presenceof a halogenation catalyst, more preferably still thionyl chloride orthionyl bromide in the presence of dimethylformamide. The thionylchloro/bromo can also act as the solvent, but more preferably thereaction takes place or in an appropriate other solvent such as toluene.In such case only stoicheometric amounts of thionyl chloride/bromidewould be required, preferably at least 2 molar equivalents, morepreferably at least 5 molar equivalents.

[0292] It is possible to undertake the four step conversion of (XX) to(XB) in a single telescoped step, without intermediate productisolation, using the same solvent throughout (hereinafter the“telescoping solvent”). Thus where X is an alkoxy group (—OR³ group),steps (XX) to (XB) can be telescoped together using a single solventsuch as a water immiscible inert organic solvent. More preferably ahydrocarbon solvent (such as toluene, xylene, anisole, chlorobenzene,hexane, heptane, octane, nonane, decane, cyclohexane, methylcyclohexane)or ethers (such as dibutyl ether, diphenyl ether) or ketones (such asmethylisobutylketone, methylethylketone) or esters (such as ethylacetate, butyl acetate) or dimethylformamide. More preferably still ahydrocarbon solvent (such as toluene, xylene, anisole, chlorobenzene,octane, nonane, decane, methylcyclohexane) or ethers (such as dibutylether, diphenyl ether) or esters (such as ethyl acetate, butyl acetate).More preferably still the telescoping solvent is toluene.

[0293] The intermediate of formula (XX) is formed from a compound offormula (XVII) in the presence of an agent which will form a protectinggroup (P) for the carboxylic acid (i.e. to form the —COP group).Preferably said agent is an esterification agent, to form a carboxylicacid ester (wherein, e.g. P will be alkoxy and the protecting formingagent will be an alcohol) such as a C₁-C₆ carboxylic acid ester whichwill be carried through the reaction scheme and hydrolised under basicconditions to the carboxylic acid function of compound (XB). Mostpreferably the esterification agent is ethanol. An additional solventsuch as toluene may be appropriate.

[0294] The intermediate of formula (XVII) is formed from2-hydroxynicotinic acid or a salt thereof in the presence of asulphonylating agent, more preferably an agent comprising SO₃ (ideallyat least 1 molar equivalent of SO₃), for example using SO₃ in an organicsolvent (e.g. THF, dioxan and heptane) or an aprotic solvent (e.g.nitrobenzene, nitromethane, 1,4-dioxane, dichloromethane) or a mineralacid as solvent (e.g. sulphuric acid) or in a liquid carboxylic acid assolvent (e.g. acetic acid) or THF or heptane. More preferably still, thesulphonylating agent is oleum (SO₃ in sulphuric acid) such as about 20%to 30% oleum.

[0295] Compounds of the general formula (IXB) are formed by the reactionof intermediates of general formula (XB) with compounds of the generalformula (VII), as detailed hereinbefore in the presence of a couplingagent, such as N,N′-carbonyldiimidazole and a suitable solvent, such asethyl acetate.

[0296] Methods for the preparation of compounds of the general formula(VII) are described hereinafter.

[0297] In a preferred embodiment of Scheme 2, X is an —OR³ alkoxy groupand so Q in compound (XIV) represents OR³. Preferably OR³ is a C₁ to C₆alkoxy group, more preferably a C₁ to C₄ primary or secondary alkoxygroup and especially ethoxy. However for other leaving groups thegeneral method for Scheme 2 would apply.

[0298] This preferred embodiment of Scheme 2 is illustrated in Scheme 3.In Scheme 3 the intermediate of formula (XB) is formed from a compoundof formula (XIV) by removal of protecting group P by a deprotectingagent, advantageously by saponification in the presence of a hydroxidebase such as sodium hydroxide, preferably in an appropriate solvent suchas water and toluene.

[0299] The intermediate of formula (XIV) is formed from a compound offormula (XV) in the presence of an appropriate C₁-C₆ alkoxidenucleophile (—OR³), (such as a primary or secondary alkoxide),preferably a metal alkoxide of the formula ZOR³, wherein the metal (Z)is as defined hereinbefore for ZOR, such as sodium ethoxide, preferablyin an appropriate solvent such as toluene or R³OH, wherein R³OH is asdefined hereinbefore and is preferably ethoxy. D in compounds offormulae (XV) and (XVI) is Cl or Br, more preferably D is Cl.

[0300] The intermediate of formula (XV) is formed from a compound offormula (XVI) by reaction with N—R¹⁰piperazine, preferably in thepresence of a base, such as triethylamine or excess N—R¹⁰piperazine,preferably in an appropriate solvent such as toluene.

[0301] The intermediate of formula (XVI) is formed from a compound offormula (XX) in the presence of a chlorinating or brominating agent asdefined for the same step in Scheme 2 such as thionyl chloride orbromide, preferably thionyl chloride or bromide/dimethylformamide. Theformer can also act as the solvent, but more preferably the reactiontakes place in an appropriate other solvent, such as toluene. In such acase only stoicheiometric amounts of thionyl chloride/bromide would berequired, preferably as at least 2 molar equivalents more preferably atleast 5 molar equivalents.

[0302] The intermediate of formula (XX) is formed from a compound offormula (XVII) in the presence of an agent which will form a protectinggroup (P) for the carboxylic acid (i.e. to form the —COP group) asdefined herein before. Preferably said agent is an esterification agent,to form a carboxylic acid ester such as a C₁-C₆ carboxylic acid esterwhich will be carried through the reaction scheme and hydrolysed underbasic conditions to the carboxylic acid function of compound (XB). Mostpreferably the esterification agent is ethanol. An additional solventsuch as toluene may be utilised as appropriate.

[0303] The intermediate of formula (XVII) is formed from2-hydroxynicotinic acid with a sulphonylating agent such as 30% oleum.

[0304] Again it is possible to undertake the four step conversion of(XX) to (XB) in a single telescoped step (as set out hereinbefore) inthe same pot, without intermediate product isolation, using the samesolvent (herein the “telescoping” solvent) throughout. The list ofsolvents described with respect to Scheme 2 are directly applicablehere. Most preferably the solvent is toluene.

[0305] For example after formation of compound (XVI), the excesschlorinating/brominating agent could be azeotroped off at the azeotropetemperature of the said agent and the telescope solvent. After formationof compound (XV), the HBr/HCl (i.e. HD) salts which are formed could bewashed out (in aqueous) or filtered from the reaction vessel and theremainder of the aqueous solvent (where applicable) azeotroped off withsome of the telescoping solvent. In the formation of compound (XIV), ifthe alkoxide used to introduce OR³ is dissolved in solvent (such asethanol), then this solvent could again be azeotroped off with some ofthe telescoping solvent. If solid alkoxide is used then this latterazeotroping step is not required. Most preferably the telescopingsolvent for any telescoped steps of scheme 3 is toluene.

[0306] It will be appreciated that salts of the compounds of Schemes 1to 3 can be formed in accordance with the invention by converting therelevant compound to a salt thereof (either in situ or as a separatestep). Also an acid addition salt of the compound of formula (I) can beformed in accordance with the invention.

[0307] 1.4. Clearly, for certain compounds of formulae (I), (IA) or (IB)wherein R¹³ is OR³, by exploiting the cyclisation and alkoxide exchangemethodology described in sections 1.2 and 2.1 herein, it may beparticularly advantageous to generate a compound of formula (I), (IA) or(IB) from a compound of the general formula (IXCa), wherein the 2-alkoxygroup of the 5-(pyridin-3-yl) substituent in the former is differentfrom that in the latter, directly in a “one-pot reaction”. To achievethis an alternative alcohol (R³OH) should be used wherein the alkylchain of the —R³ group of the alcohol is different from that of the—R^(3a) group on the starting compound of general formula (IXCa). Whenthe alcohol which is to provide the alternative 2-alkoxy group (—OR³) istoo scarce or expensive to be employed as the reaction solvent, then itwill be expedient to use a suitable alternative such as 1,4-dioxan asreaction solvent with the required alcohol (R^(3a)OH) present in anamount sufficient to effect the desired conversion, typically from about1 to about 2 molecular equivalents. (IXCa) and R^(3a) are as definedhereinbefore.

[0308] 2. In a further generally applicable process, compounds of thegeneral formula (I), (IA) or (IB) may be prepared from “alternative”compounds of the general formula (I), (IA) or (IB) wherein said processmay comprise either interconversion of differing —OR³ groups,interconversion of X and —OR³ groups or interconversion of —OR³ and—NR⁵R⁶ groups wherein X, R³ and NR⁵R⁶ are as defined hereinbefore.

[0309] 2.1 As mentioned earlier, certain compounds of formulae (I), (IA)and (IB) can be interconverted by inducing alkoxide exchange ordisplacement at the 2-position of the 5-(pyridin-3-yl) substituent. Thismay be achieved, by treating the appropriate alcohol (of formulaR^(3a)OH wherein the R^(3a) alkyl group is as defined hereinbefore andis different from the R³ group on the starting material (I), (IA) or(IB) with an alkali metal salt of a sterically hindered alcohol or aminein order to generate the required alkoxide anion which then reacts withthe substrate. Typically, in a two-step procedure, a mixture of fromabout 1 to about 8, more preferably from about 5 to about 8, andespecially from about 4 to about 8 molecular equivalents of potassiumbis(trimethylsilyl)amide and the required alcohol (of formula R^(3a)OH)as solvent is heated at from about 80° C. to about 100° C. for about 25minutes to about 1 hour, followed by addition of the compound of formula(IA) or (IB) and heating of the reaction mixture at from about 100° C.to about 130° C. for from about 6 to about 24 hours. Alternatively, in aone-step procedure, the substrate may be treated directly, in therequired alcohol as solvent, with from about 1.2 to about 6, preferablyfrom about 4 to about 6 molecular equivalents of, for example, potassiumbis(trimethylsilyl)amide, potassium t-butoxide or cesium carbonate atfrom about 80° C. to about 130° C. A hydroxide trapping agent may beoptionally included in such alkoxide exchange reactions.

[0310] 2.2 Alternatively, certain compounds of the general formula (I),(IA) or (IB) wherein R¹³ is —OR³ may be obtained from compounds of thegeneral formula (XXX):

[0311] wherein R¹, R², R⁴ are as defined previously herein and wherein Xis anything other than —OR³ by reaction in the presence of —OR³⁻optionally in the presence of a hydroxide trapping agent as definedhereinbefore.

[0312] 2.3 In a yet further alternative synthesis compounds of thegeneral formula (I), (IA) or (IB) wherein R¹³ is NR⁵R⁶ may be generateddirectly from a compound of general formula (I) wherein R¹³=OR³. WhenR¹³ is OR³, the substrate may be treated with an excess of R⁵R⁶NH, or asuitable acid addition salt thereof, in the presence of an excess of anon-nucleophilic base such as a sterically hindered amine or a suitableinorganic base in a suitable solvent. Typically, R⁵R⁶NH is used as thefree base with about a 3-fold excess (over the substrate) of potassiumbis(trimethylsilyl)amide (KHMDS) in dimethylformamide (DMF) as solventat about 100° C. Alternatively, an excess of R⁵R⁶NH may be used as thesolvent and the reaction conducted in the presence of about a 50% excessof copper(II) sulphate at up to the reflux temperature of the reactionmedium. Where the desired amino substituent on the compound of theformula (I), (IA) or (IB) is —NR⁵R⁶ and one of either R⁵ or R⁶ is H,then the exchange reaction may be carried out by refluxing with theappropriate amine, and copper(II) sulphate penta- or hepta-hydrate oranhydrous copper (II) sulphate or KHDMS in DMF. Typically, to exchangethe OR³ group for alternative amines of the formula NHR⁵R⁶, such ascompounds wherein R⁵ or R⁶ are selected from aliphatic or cyclic amines,optionally including oxygen (e.g. morpholine), then the reaction ispreferably carried out by treating with the appropriate amine and about3 equivalents of potassium bis(trimethylsilyl)amide in DMF for about 18hours at 100° C.

[0313] 3. In a yet further alternative process, a compound of thegeneral formula (I) may be prepared from a compound of general formulae(IIA) or (IIC) respectively:

[0314] wherein Y is halo, preferably chloro, and R¹, R², R³, R⁵ and R⁶are as previously defined for formulae (IXA) and (IXC), by a reactionwith a 4-R¹⁰-piperazinyl compound as described for the preparation ofcompounds of formula (XA) and (XB) from compounds of formula (VIIA) and(VIIIB) respectively.

[0315] Alternatively, a compound of the general formula (I), (IA) or(IB) may be prepared from a compound of the general formula (IIB):

[0316] wherein R¹, R², R⁴ and X are as previously defined herein viareaction with a 4-R¹⁰ piperazinyl compound followed by an optionaldisplacement reaction in the presence of a hydroxide trapping agent and—OR³— as detailed hereinbefore for the preparation of compound (I) fromcompound (IXB) or (XXX).

[0317] 3.1 A compound of general formulae (IIA) or (IIB) or (IIC) may beprepared from a compound of general formula (IVA) or (IVB) or (IVC)respectively:

[0318] wherein R¹, R², R³, R⁵, R⁶ and X are as previously herein, by theapplication of known methods for converting amino to a SO₂Y groupwherein Y is also as previously defined for formulae (IIA), (IIB) and(IIC). Such reactions are previously described for the preparation ofcompounds of the general formulae (VIIIA) and (VIIIB) from compounds ofthe general formulae (XIA) and (XIB) respectively.

[0319] A compound of the general formula (IVA) or (IVB) or (IVC) may beprepared by cyclisation of a compound of the general formula (VA) or(VB) or (VC) respectively:

[0320] wherein R¹, R², R³, R⁵, R⁶ and X are as previously defined hereinand wherein the conditions for cyclisation are analogous to thosepreviously described for cyclisation of the compounds of generalformulae (IXA), (IXB) or (IXC).

[0321] A compound of formula (VA) or (VB) or (VC) may be prepared byreduction of a compound of formula (VIA) or (VIB) or (IVC) respectively:

[0322] wherein R¹, R², R³, R⁵, R⁶ and X are as previously defined forcompounds of the general formulae (VA), (VB) and (VC), by conventionalcatalytic or catalytic transfer hydrogenation procedures as previouslydetailed for preparation of compounds of the general formulae (XIA) or(XIB) from compounds of the general formulae (XIIA) or (XIIB)respectively.

[0323] A compound of formula (VIA), (VIB) or (VIC) may be prepared byreaction of a compound of formula (VII) as defined previously hereinwith a compound of formula (XIIA) or (XIIB) or (XIIC) respectively:

[0324] wherein R³, R⁵, R⁶ and X are as previously defined for compoundsof the general formulae (VIA) or (VIB) or (VIC). Again, as previouslydetailed a conventional amine protecting group strategy is preferred for(XIIA) when NR⁵R⁶ is a primary or secondary amino group. The couplingreaction is analogous to the reactions of (VII) with the compounds ofgeneral formulae (XA) or (XB) or (XC) already described herein.

[0325] 3.2 A compound of general formulae (IIA) or (IIB) or (IIC) may beprepared from a compound of formula (IVA) or (IVB) or (IVC) respectivelyas described hereinbefore wherein said compound of the general formulae(IVA) or (IVB) or (IVC) may be prepared by direct cyclisation of acompound of the general formula (VIA) or (VIB) or (VIC) respectively:

[0326] wherein R¹, R², R³, R⁵, R⁶ and X are as previously herein andwherein the conditions for said direct cyclisation are analogous to thepreviously described cyclisation for compounds of the general formulae(IXA) or (IXB) or (IXC) and wherein said cyclisation is followed byreduction of the resultant intermediate compounds according to themethods previously detailed herein to provide compounds of the generalformulae (IVA) or (IVB) or (IVC) from compounds of the general formulae(VA) or (VB) or (VC).

[0327] Compounds of the general formula (XIIC) wherein X is Cl may beprepared from 2-hydroxy nicotinic acid via nitration followed byesterification then chlorination of the suitably protected nicotinicacid and subsequent ester hydrolysis.

[0328] Compounds of the general formula (XIIIC) (i.e. compounds ofgeneral formula (XIIIB wherein X is —OR³) can be prepared by analogywith the methods detailed previously herein.

[0329] 4. A further, generally applicable, synthetic route to compoundsof the general formula (I), (IA) or (IB) involves incorporation of theR¹ substituent in the final step of the synthesis. Thus a compound ofthe general formula (I), (IA) or (IB) may be prepared by alkylation of acompound of formula (Ia), (lAa) or (IBa) wherein R¹ is hydrogen and R²,R¹³ and R⁴ are as previously defined for formulae (I), (IA) and (IB),using one or more of a plethora of well-known methods, such as:

[0330] (i) reaction with a compound of formula R¹J, wherein R¹ is aspreviously defined for compounds of general formulae (I), (IA) and (IB),and J is a suitable leaving group, e.g. halo (preferably chloro, bromoor iodo), C₁-C₄ alkanesulphonyloxy, trifluoromethanesulphonyloxy orarylsulphonyloxy (such as benzenesulphonyloxy or p-toluenesulphonyloxy),in the presence of an appropriate base, optionally in the presence ofsodium iodide or potassium iodide, at from about −70° C. to about 100°C. Preferably the alkylation is conducted at from about room temperatureto about 120° C. Suitable base-solvent combinations may be selectedfrom:

[0331] (a) sodium, potassium or cesium carbonate, sodium or potassiumbicarbonate, or a tertiary amine such as triethylamine or pyridine,together with a C₁ to C₄ alkanol, 1,2-dimethoxyethane, tetrahydrofuran,1,4-dioxan, acetonitrile, pyridine, N,N-dimethylformamide orN,N-dimethylacetamide;

[0332] (b) sodium or potassium hydroxide, or a sodium or potassium C₁ toC₄ alkoxide, together with a C₁ to C₄ alkanol, water or mixturesthereof;

[0333] (c) lithium, sodium or potassium hydride, lithium, sodium orpotassium bis(trimethylsilyl)amide, lithium diisopropylamide orbutyllithium, together with toluene, ether, 1,2-dimethoxyethane,tetrahydrofuran or 1,4-dioxan; or

[0334] (d) under phase transfer catalysis conditions, atetraalkylammonium halide or hydroxide, together with a mixture of anaqueous solution of sodium or potassium hydroxide and dichloromethane,1,2-dichloroethane or chloroform;

[0335] Typically, either about a 10% excess of sodium hydride is addedto a solution of the substrate in a suitable solvent, e.g. anhydroustetrahydrofuran or cesium carbonate in dimethylformamide (DMF) isemployed, and the resulting anion treated with about a 10% excess of therequired R¹J.

[0336] (ii) reaction with a compound of formula R¹OH, wherein R¹ is aspreviously defined for compounds of the general formulae (I), (IA) and(IB), using classical Mitsunobu methodology. Typical reaction conditionsinvolve treating the substrate with the alkanol in the presence of atriarylphosphine and a di(C₁ to C₄)alkyl azodicarboxylate, in a suitablesolvent such as tetrahydrofuran or 1,4-dioxan, at from about −5° C. toabout room temperature.

[0337] (iii) reaction with a compound of formula R¹M, wherein R¹represents optionally substituted phenyl, Het², Het³ or Het⁴ and whereinsaid Het groups are either aromatic or partially unsaturated at the Catom that is attached to M, and wherein M represents an optionallysubstituted metal or boron group wherein said metal or boron group issuitable for cross-coupling reactions (of metal or boron compounds), forexample a dihydroxyborane, in the presence of an appropriate catalystsystem (e.g. copper (II) acetate) or under so-called “Goldberg”conditions. Such cross-coupling is preferably carried out in thepresence of a suitable base (e.g. pyridine), and a drying agent,typically 4 Å molecular sieves, in a suitable solvent such asdichloromethane or N-methylpyrrolidine, and optionally under microwaveirradiation.

[0338] (iv) reaction with a compound of formula R¹E, where E is halo,preferably bromo, under conditions suitable for cross-coupling ofhalogenated compounds, where R¹ is as defined in (iii). Such reaction istypically carried out in the presence of an appropriate catalyst system(e.g. Palladium catalyst), in the presence of a suitable base, such asfor example sodium t-butoxide, in a suitable solvent, such as toluene,with heating, typically at about 70° C.

[0339] 4.1 Thus, a compound of general formula (I^(a)), (IA^(a)) or(IB^(a)), wherein R¹ is hydrogen and R², R¹³ and R⁴ are as previouslydefined for compounds of general formulae (I), (IA) or (IB), may beobtained from a compound of formula (IXA^(a)) or (IXB^(a)) or (IXC^(a))respectively wherein R¹ is hydrogen, and R², R³, R⁵, R⁶ and R⁴ and X areas previously defined for formulae (IXA), (IXB) or (IXC), under the sameconditions as those used for the conversion of a compound of the generalformula (IXA), (IXB) or (IXC) to a compound of the general formula (I),(IA) or (IB) respectively when R¹ is other than hydrogen, followed byacidification of the reaction mixture to a pH of about 6.

[0340] 4.2 In a further alternative, generally applicable syntheticroute the compounds of the present invention may be prepared bycyclisation of compounds of the general formulae (IXA), (IXB) or (IXC)wherein said compounds of the general formulae (IXA), (IXB) or (IXC) areobtained from compounds of the general formulae (IXA^(a)), (IXB^(a)) or(IXC^(a)) wherein R¹ is hydrogen and R², R³, R⁵, R⁶ and R⁴ are aspreviously defined herein, using one or more of a plethora of well-knownmethods such as are detailed hereinbefore for conversion of compounds ofthe general formulae (I^(a)), (IA^(a)) and (IB^(a)) to compounds of thegeneral formulae (I), (IA) and (IB). Any of the previously detailedmethods for such general conversion may be used. Preferred conditionsfor such conversion use either from about 1.0 to 1.3 equivalents ofsodium hydride in tetrahydrofuran solvent at from about −78° to aboutroom temperature and from about 1.1 to about 2.3 equivalents ofalkylating agent at from about 60° C. to about 70° C., or from about 2.2equivalents of cesium carbonate as base in dimethylformamide as solventand about 1.1. equivalent of alkylating agent at about 60° C.

[0341] 5. In a yet further alternative synthesis, compounds of thegeneral formula (I), (IA) or (IB) can be obtained from compounds of thegeneral formula (I) wherein R¹⁰ is H, via a suitable alkylation reactionsuch as for example with an alkyl halide and a suitable base e.g. cesiumcarbonate and methyl chloride.

[0342] In a preferred process for the preparation of the compoundsaccording to the present invention compounds of general formula (VIIB)are prepared from compounds of the general formula (XIIIB) according tothe process detailed in Preparations 96(a) to (h). These compounds ofgeneral formula (VIIB) are coupled with compounds of general formula(XC) according to the process detailed in Preparations 29 and 96(i) toprovide a compound of general formula (IXC), wherein said compound ofgeneral formula (IXC) is prepared according to the process detailed inPreparation 95. The compound of general formula (IXC) is then preferablycyclised under basic conditions according to the process detailed inExamples 8 and 102 to form compounds of general formula (IB) wherein R¹³is OR³.

[0343] The 4-aminopyrazole-5-carboxamides of general formulae (VII),(VIIA) and (VIIB), the pyrazoles of general formula (XIII), thecarboxylic acids of formulae (XA), (XB), (XIIA), (XIIB), (XIIC), (VIIA),(VIIB), (VIIC) and (X), or the compounds of the general formula R¹J andR¹E when neither commercially available nor subsequently described, canbe obtained either by analogy with the processes described in thePreparations section or by conventional synthetic procedures, inaccordance with standard textbooks on organic chemistry or literatureprecedent, from readily accessible starting materials using appropriatereagents and reaction conditions.

[0344] Moreover, persons skilled in the art will be aware of variationsof, and alternatives to, those processes described hereinafter in theExamples and Preparations sections which allow the compounds defined byformulae (I), (IA) or (IB) to be obtained.

[0345] The pharmaceutically acceptable acid addition salts of thecompounds of formulae (I), (IA) or (IB) which contain a basic centre mayalso be prepared in a conventional manner. By way of illustration, acidaddition salts of compounds of formula (I) (more particularly IA and IB)can be formed by reacting a compound of formula (I) with an equimolar orexcess amount of the appropriate acid, either neat or in a suitablesolvent. The salt may then be precipitated out of solution and isolatedby filtration or the reaction solvent can be stripped off byconventional means such as by evaporation under vacuum. Typical saltswhich can be used in the schemes of 1 to 3 are given in PCT/IB99/00519.Example of salts of compounds IA and IB are the p-toluenesulfonate,benzenesulfonate, camphorsulfonate and ethanesulfonate respectively.

[0346] Pharmaceutically acceptable base addition salts can be obtainedin an analogous manner by treating a solution of a compound of formula(I), (IA) or (IB) with the appropriate base. Both types of salt may beformed or interconverted using ion-exchange resin techniques.

[0347] The present invention also includes all suitable isotopicvariations of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof. An isotopic variation of a compound of theformula (I) or a pharmaceutically acceptable salt thereof is defined asone in which at least one atom is replaced by an atom having the sameatomic number but an atomic mass different from the atomic mass usuallyfound in nature. Examples of isotopes that can be incorporated intocompounds of the formula (I) and pharmaceutically acceptable saltsthereof include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁷O, ¹⁸O0, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Certainisotopic variations of the compounds of the formula (I) andpharmaceutically acceptable salts thereof, for example, those in which aradioactive isotope such as ³H or ¹⁴C is incorporated, are useful indrug and/or substrate tissue distribution studies. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withisotopes such as deuterium, i.e., ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements and hence maybe preferred in some circumstances. Isotopic variations of the compoundsof formula (I) and pharmaceutically acceptable salts thereof of thisinvention can generally be prepared by conventional procedures such asby the illustrative methods or by the preparations described in theExamples and Preparations hereafter using appropriate isotopicvariations of suitable reagents.

[0348] It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of the formulae (I), (IA) or (IB),which may be made prior to a final de-protection stage, may not possesspharmacological activity as such, but may, in certain instances, beadministered orally or parenterally and thereafter metabolised in thebody to form compounds of the invention which are pharmacologicallyactive. Such derivatives may therefore be described as “pro-drugs”.Further, certain compounds of the formulae (I), (IA) or (IB) may act aspro-drugs of other compounds of the formulae (I), (IA) or (IB).

[0349] All protected derivatives, and pro-drugs, of compounds of generalformulae (I), (IA) or (IB) are included within the scope of theinvention. Suitable protecting groups for use in accordance with theinvention can be found in “Protecting Groups” edited by P. J. Kocienski,Thieme, New York, 1994—see particularly chapter 4, page 118-154 forcarboxy protecting groups; and “Protective Groups in Organic Synthesis”2^(nd) edition, T. W. Greeene & P. G. M. Wutz, Wiley-Interscience(1991)—see particularly chapter 5 for carboxy protecting groups.Examples of suitable pro-drugs for the compounds of the presentinvention are described in Drugs of Today, Volume 19, Number 9, 1983,pp.499-538 and in Topics in Chemistry, Chapter 31, pp 306-316.

[0350] The biological activities of the compounds of the presentinvention were determined by the following test methods.

[0351] Phosphodiesterase (PDE) Inhibitory Activity

[0352] The compounds of the present invention are potent and selectivecGMP PDE5 inhibitors. In vitro PDE inhibitory activities against cyclicguanosine 3′,5′-monophosphate (cGMP) and cyclic adenosine3′,5′-monophosphate (cAMP) phosphodiesterases were determined bymeasurement of their IC₅₀ values (the concentration of compound requiredfor 50% inhibition of enzyme activity).

[0353] The required PDE enzymes were isolated from a variety of sources,including human corpus cavernosum, human and rabbit platelets, humancardiac ventricle, human skeletal muscle and bovine retina, essentiallyby the method of W. J. Thompson and M. M. Appleman (Biochem., 1971, 10,311). In particular, the cGMP-specific PDE (PDE5) and the cGMP-inhibitedcAMP PDE (PDE3) were obtained from human corpus cavernosum tissue, humanplatelets or rabbit platelets; the cGMP-stimulated PDE (PDE2) wasobtained from human corpus cavernosum; the calcium/calmodulin(CalCAM)-dependent PDE (PDE1) from human cardiac ventricle; thecAMP-specific PDE (PDE4) from human skeletal muscle; and thephotoreceptor PDE (PDE6) from bovine retina. Phosphodiesterases 7-11were generated from full length human recombinant clones transfectedinto SF9 cells.

[0354] Assays were performed either using a modification of the “batch”method of W. J. Thompson et al. (Biochem., 1979, 18, 5228) or using ascintillation proximity assay for the direct detection of AMP/GMP usinga modification of the protocol described by Amersham plc under productcode TRKQ7090/7100. In summary, the effect of PDE inhibitors wasinvestigated by assaying a fixed amount of enzyme in the presence ofvarying inhibitor concentrations and low substrate, (cGMP or cAMP in a3:1 ratio unlabelled to [³H]-labeled at a conc ˜1/3 K_(m)) such thatIC₅₀≅K_(i). The final assay volume was made up to 100 μl with assaybuffer [20 mM Tris-HCl pH 7.4, 5 mM MgCl₂, 1 mg/ml bovine serumalbumin]. Reactions were initiated with enzyme, incubated for 30-60 minat 30° C. to give <30% substrate turnover and terminated with 50 μlyttrium silicate SPA beads (containing 3 mM of the respective unlabelledcyclic nucleotide for PDEs 9 and 11). Plates were re-sealed and shakenfor 20 min, after which the beads were allowed to settle for 30 min inthe dark and then counted on a TopCount plate reader (Packard, Meriden,Conn.) Radioactivity units were converted to % activity of anuninhibited control (100%), plotted against inhibitor concentration andinhibitor IC₅₀ values obtained using the ‘Fit Curve’ Microsoft Excelextension. Results from these tests show that the compounds of thepresent invention are potent and selective inhibitors of cGMP-specificPDE5.

[0355] Preferred compounds of the present invention, such as those ofExamples 3-12, 14-17, 19, 21-30, 32, 33, 35-46, 48-59, 61, 62, 65-75,77, 79-102 have IC₅₀ values of less than about 10 nM for the PDE5enzyme. More preferred compounds, such as those of Examples 3-12, 14,15, 17, 23-30, 32, 33, 35-46, 48, 50-59, 61, 62, 65, 69-74, 79-102 haveIC₅₀ values of less than about 5 nM for the PDE5 enzyme. Especiallypreferred compounds, such as those of Examples 4-10, 15, 17, 23-28, 30,32, 33, 35-42, 44, 45, 46, 50, 52-56, 58, 59, 61, 62, 65, 69-74, 79-93,96, 98-102 have IC₅₀ values of less than about 2 nM for the PDE5 enzyme.

[0356] Especially preferred herein are compounds which have an IC₅₀value of less than about 10, more preferably less than about 5, and mostpreferably less than about 2 nM for the PDE5 enzyme in combination withselectivity of greater than 10-fold, more preferably greater than50-fold, more preferably greater than 100-fold and especially greaterthan 200-fold selectivity for the. PDE5 enzyme versus the PDE6 enzyme.

[0357] Functional Activity

[0358] This was assessed in vitro by determining the capacity of acompound of the invention to enhance sodium nitroprusside-inducedrelaxation of pre-contracted rabbit corpus cavernosum tissue strips, asdescribed by S. A. Ballard et al. (Brit. J. Pharmacol., 1996, 118(suppl.), abstract 153P).

[0359] In Vivo Activity

[0360] Compounds were screened in anaesthetised dogs to determine theircapacity, after i.v. administration, to enhance the pressure rises inthe corpora cavernosa of the penis induced by intracavernosal injectionof sodium nitroprusside, using a method based on that described byTrigo-Rocha et al. (Neurourol. and Urodyn., 1994,13, 71).

[0361] The compounds of formulae (I), (IA) or (1B), theirpharmaceutically acceptable salts, and pharmaceutically acceptablesolvates of either entity can be administered alone but, in humantherapy will generally be administered in admixture with a suitablepharmaceutical excipient diluent or carrier selected with regard to theintended route of administration and standard pharmaceutical practice.For example, the compounds of formulae (I), (IA) or (1B) or salts orsolvates thereof can be administered orally, buccally or sublingually inthe form of tablets, capsules (including soft gel capsules), ovules,elixirs, solutions or suspensions, which may contain flavouring orcolouring agents, for immediate-, delayed-, modified-, orcontrolled-release such as sustained-, dual-, or pulsatile deliveryapplications. The compounds of the invention may also be administeredvia intracavernosal injection. The compounds of the invention may alsobe administered via fast dispersing or fast dissolving dosages forms orin the form of a high energy dispersion or as coated particles. Suitablepharmaceutical formulations of the compounds of the invention may be incoated or un-coated form as desired.

[0362] Such tablets may contain excipients such as microcrystallinecellulose, lactose, sodium citrate, calcium carbonate, dibasic calciumphosphate, glycine and starch (preferably corn, potato or tapiocastarch), disintegrents such as sodium starch glycollate, croscarmellosesodium and certain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, stearic acid, glycerylbehenate and talc may be included.

[0363] Solid compositions of a similar type may also be employed asfillers in gelatin capsules. Preferred excipients in this regard includelactose, starch, a cellulose, milk sugar or high molecular weightpolyethylene glycols. For aqueous suspensions and/or elixirs, thecompounds of the formula (I), (IA) or (IB) may be combined with varioussweetening or flavouring agents, colouring matter or dyes, withemulsifying and/or suspending agents and with diluents such as water,ethanol, propylene glycol and glycerin, and combinations thereof.

[0364] Modified release and pulsatile release dosage forms may containexcipients such as those detailed for immediate release dosage formstogether with additional excipients that act as release rate modifiers,these being coated on and/or included in the body of the device. Releaserate modifiers include, but are not exclusively limited to,hydroxypropylmethyl cellulose, methyl cellulose, sodiumcarboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethyleneoxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer,hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acidcopolymer and mixtures thereof. Modified release and pulsatile releasedosage forms may contain one or a combination of release rate modifyingexcipients. Release rate modifying excipients maybe present both withinthe dosage form i.e. within the matrix, and/or on the dosage form i.e.upon the surface or coating.

[0365] Fast dispersing or dissolving dosage formulations (FDDFs) maycontain the following ingredients: aspartame, acesulfame potassium,citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethylacrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose,magnesium stearate, mannitol, methyl methacrylate, mint flavouring,polyethylene glycol, fumed silica, silicon dioxide, sodium starchglycolate, sodium stearyl fumarate, sorbitol, xylitol. The termsdispersing or dissolving as used herein to describe FDDFs are dependentupon the solubility of the drug substance used i.e. where the drugsubstance is insoluble a fast dispersing dosage form can be prepared andwhere the drug substance is soluble a fast dissolving dosage form can beprepared.

[0366] The compounds of the invention can also be administeredparenterally, for example, intracavernosally, intravenously,intra-arterially, intraperitoneally, intrathecally, intraventricularly,intraurethrally intrasternally, intracranially, intramuscularly orsubcutaneously, or they may be administered by infusion or needlessinjection techniques. For such parenteral administration they are bestused in the form of a sterile aqueous solution which may contain othersubstances, for example, enough salts or glucose to make the solutionisotonic with blood. The aqueous solutions should be suitably buffered(preferably to a pH of from 3 to 9), if necessary. The preparation ofsuitable parenteral formulations under sterile conditions is readilyaccomplished by standard pharmaceutical techniques well-known to thoseskilled in the art.

[0367] For oral and parenteral administration to human patients, thedaily dosage level of the compounds of formula (I), (IA) or (1B) orsalts or solvates thereof will usually be from 10 to 500 mg (in singleor divided doses).

[0368] Thus, for example, tablets or capsules of the compounds offormulae (I), (IA) or (IB) or salts or solvates thereof may contain from5 mg to 250 mg of active compound for administration singly or two ormore at a time, as appropriate. The physician in any event willdetermine the actual dosage which will be most suitable for anyindividual patient and it will vary with the age, weight and response ofthe particular patient. The above dosages are exemplary of the averagecase. There can, of course, be individual instances where higher orlower dosage ranges are merited and such are within the scope of thisinvention. The skilled person will also appreciate that, in thetreatment of certain conditions (including MED and FSD), compounds ofthe invention may be taken as a single dose on an “as required” basis(i.e. as needed or desired).

[0369] Example 10 mg Tablet Formulation Ingredient % w/w Besylate saltof Example 103 13.038* Lactose 62.222 Starch 20.740 CroscarmelloseSodium 3.000 Magnesium Stearate 1.000

[0370] Such tablets can be manufactured by standard processes, forexample, direct compression or a wet or dry granulation process. Thetablet cores may be coated with appropriate overcoats.

[0371] The compounds of the invention can also be administeredintranasally or by inhalation and are conveniently delivered in the formof a dry powder inhaler or an aerosol spray presentation from apressurised container, pump, spray or nebuliser with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark] or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbondioxide or other suitable gas. In the case of a pressurised aerosol, thedosage unit may be determined by providing a valve to deliver a meteredamount. The pressurised container, pump, spray or nebuliser may containa solution or suspension of the active compound, e.g. using a mixture ofethanol and the propellant as the solvent, which may additionallycontain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges(made, for example, from gelatin) for use in an inhaler or insufflatormay be formulated to contain a powder mix of a compound of the formula(I), (IA) or (IB) and a suitable powder base such as lactose or starch.

[0372] Aerosol or dry powder formulations are preferably arranged sothat each metered dose or “puff” contains from 1 to 50 mg of a compoundof the formula (I), (IA) or (IB) for delivery to the patient. Theoverall daily dose with an aerosol will be in the range of from 1 to 50mg which may be administered in a single dose or, more usually, individed doses throughout the day.

[0373] The compounds of the invention may also be formulated fordelivery via an atomiser. Formulations for atomiser devices may containthe following ingredients as solubilisers, emulsifiers or suspendingagents: water, ethanol, glycerol, propylene glycol, low molecular weightpolyethylene glycols, sodium chloride, fluorocarbons, polyethyleneglycol ethers, sorbitan trioleate, oleic acid.

[0374] Alternatively, the compounds of the formulae (I), (IA) or (IB) orsalts or solvates thereof can be administered in the form of asuppository or pessary, or they may be applied topically in the form ofa gel, hydrogel, lotion, solution, cream, ointment or dusting powder.The compounds of the formulae (IA) and (IB) or salts or solvates thereofmay also be dermally administered. The compounds of the formulae (I),(IA) or (IB) or salts or solvates thereof may also be transdermallyadministered, for example, by the use of a skin patch. They may also beadministered by the ocular, pulmonary or rectal routes.

[0375] For ophthalmic use, the compounds can be formulated as micronisedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.Alternatively, they may be formulated in an ointment such as petrolatum.

[0376] For application topically to the skin, the compounds of theformulae (I), (IA) or (IB) or salts or solvates thereof can beformulated as a suitable ointment containing the active compoundsuspended or dissolved in, for example, a mixture with one or more ofthe following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water. Alternatively, they can be formulated as a suitablelotion or cream, suspended or dissolved in, for example, a mixture ofone or more of the following: mineral oil, sorbitan monostearate, apolyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0377] The compounds of the formulae (I), (IA) or (IB) may also be usedin combination with a cyclodextrin. Cyclodextrins are known to forminclusion and non-inclusion complexes with drug molecules. Formation ofa drug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described inWO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

[0378] Generally, in humans, oral administration of the compounds of theinvention is the preferred route, being the most convenient and, forexample in MED, avoiding the well-known disadvantages associated withintracavernosal (i.c.) administration. A preferred oral dosing regimenin MED for a typical man is from 5 to 250 mg of compound when required.In circumstances where the recipient suffers from a swallowing disorderor from impairment of drug absorption after oral administration, thedrug may be administered parenterally, sublingually or buccally.

[0379] For veterinary use, a compound of formula (I), (IA) or (IB), or aveterinarily acceptable salt thereof, or a veterinarily acceptablesolvate or pro-drug thereof, is administered as a suitably acceptableformulation in accordance with normal veterinary practice and theveterinary surgeon will determine the dosing regimen and route ofadministration which will be most appropriate for a particular animal.

[0380] It is to be appreciated that all references herein to treatmentinclude curative, palliative and prophylactic treatment.

[0381] Thus the invention provides a pharmaceutical compositioncomprising a compound of formula (I), (IA) or (IB), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate or pro-drug thereof, together with a pharmaceuticallyacceptable diluent or carrier.

[0382] It further provides a veterinary formulation comprising acompound of formula (I), (IA) or (IB), or a veterinarily acceptable saltthereof, or a veterinarily acceptable solvate or pro-drug thereof,together with a veterinarily acceptable diluent or carrier.

[0383] The invention also provides a compound of formula (I), (IA) or(IB), or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate or pro-drug thereof, or apharmaceutical composition containing any of the foregoing, for use as ahuman medicament.

[0384] In addition, it provides a compound of formula (I), (IA) or (IB),or a veterinarily acceptable salt thereof, or a veterinarily acceptablesolvate or pro-drug thereof, or a veterinary formulation containing anyof the foregoing, for use as an animal medicament.

[0385] In yet another aspect, the invention provides the use of acompound of formula (I), (IA) or (IB), or a pharmaceutically acceptablesalt thereof, or a pharmaceutically acceptable solvate or pro-drugthereof, for the manufacture of a human medicament for the curative,palliative or prophylactic treatment of a medical condition for which acGMP PDE5 inhibitor is indicated. There is further provided the use of acompound of formula (I), (IA) or (IB) or a suitable salt, solvate orpro-drug thereof, in the manufacture of a medicament for the treatmentof a medical condition in which inhibition of a cGMP PDE5 is desirable.

[0386] It also provides the use of a compound of formula (I), (IA) or(IB), or a veterinarily acceptable salt thereof, or a veterinarilyacceptable solvate or pro-drug thereof, for the manufacture of an animalmedicament for the curative, palliative or prophylactic treatment of amedical condition for which a cGMP PDE5 inhibitor is indicated.

[0387] Moreover, the invention provides the use of a compound of formula(I), (IA) or (IB), or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate or pro-drug thereof, for themanufacture of a human medicament for the curative, palliative orprophylactic treatment of male erectile dysfunction (MED), impotence,female sexual dysfunction (FSD), clitoral dysfunction, female hypoactivesexual desire disorder, female sexual arousal disorder, female sexualpain disorder, female sexual orgasmic dysfunction (FSOD), sexualdysfunction due to spinal cord injury, selective serotonin re-uptakeinhibitor (SSRI) induced sexual dysfunction, premature labour,dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outletobstruction, incontinence, stable, unstable and variant (Prinzmetal)angina, hypertension, pulmonary hypertension, chronic obstructivepulmonary disease, coronary artery disease, congestive heart failure,atherosclerosis, conditions of reduced blood vessel patency, peripheralvascular disease, stroke, nitrate induced tolerance, bronchitis,allergic asthma, chronic asthma, allergic rhinitis, diseases andconditions of the eye, diseases characterised by disorders of gutmotility, pre-eclampsia, Kawasaki's syndrome, nitrate tolerance,multiple sclerosis, diabetic nephropathy, neuropathy including autonomicand peripheral neuropathy and in particular diabetic neuropathy andsymptoms thereof e.g. gastroparesis, Alzheimer's disease, acuterespiratory failure, psoriasis, skin necrosis, cancer, metastasis,baldness, nutcracker oesophagus, anal fissure, haemorrhoids, hypoxicvasoconstriction or blood pressure stabilisation during haemodialysis.Particularly preferred conditions include MED and FSD.

[0388] It also provides the use of a compound of formula (I), (IA) or(IB), or a veterinarily acceptable salt thereof, or a veterinarilyacceptable solvate or pro-drug thereof, for the manufacture of an animalmedicament for the curative, palliatve or prophylactic treatment of maleerectile dysfunction (MED), impotence, female sexual dysfunction (FSD),clitoral dysfunction, female hypoactive sexual desire disorder, femalesexual arousal disorder, female sexual pain disorder, female sexualorgasmic dysfunction (FSOD), sexual dysfunction due to spinal cordinjury, selective serotonin re-uptake inhibitor (SSRI) induced sexualdysfunction, premature labour, dysmenorrhoea, benign prostatichyperplasia (BPH), bladder outlet obstruction, incontinence, stable,unstable and variant (Prinzmetal) angina, hypertension, pulmonaryhypertension, chronic obstructive pulmonary disease, coronary arterydisease, congestive heart failure, atherosclerosis, conditions ofreduced blood vessel patency, peripheral vascular disease, stroke,nitrate induced tolerance, bronchitis, allergic asthma, chronic asthma,allergic rhinitis, diseases and conditions of the eye, diseasescharacterised by disorders of gut motility, pre-eclampsia, Kawasaki'ssyndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy,neuropathy including autonomic and peripheral neuropathy and inparticular diabetic neuropathy and symptoms thereof, Alzheimer'sdisease, acute respiratory failure, psoriasis, skin necrosis, cancer,metastasis, baldness, nutcracker oesophagus, anal fissure, haemorrhoids,hypoxic vasoconstriction or blood pressure stabilisation duringhaemodialysis. Particularly preferred conditions include MED and FSD.

[0389] Additionally, the invention provides a method of treating orpreventing a medical condition for which a cGMP PDE5 inhibitor isindicated, in a mammal (including a human being), which comprisesadministering to said mammal a therapeutically effective amount of acompound of formula (I), (IA) or (IB), or a tolerance, multiplesclerosis, diabetic nephropathy, neuropathy including autonomic andperipheral neuropathy and in particular diabetic neuropathy and symptomsthereof e.g. gastroparesis, Alzheimer's disease, acute respiratoryfailure, psoriasis, skin necrosis, cancer, metastasis, baldness,nutcracker oesophagus, anal fissure, haemorrhoids, hypoxicvasoconstriction or blood pressure stabilisation during haemodialysis.Particularly preferred conditions include MED and FSD.

[0390] It also provides the use of a compound of formula (I), (IA) or(IB), or a veterinarily acceptable salt thereof, or a veterinarilyacceptable solvate or pro-drug thereof, for the manufacture of an animalmedicament for the curative, palliatve or prophylactic treatment of maleerectile dysfunction (MED), impotence, female sexual dysfunction (FSD),clitoral dysfunction, female hypoactive sexual desire disorder, femalesexual arousal disorder, female sexual pain disorder, female sexualorgasmic dysfunction (FSOD), sexual dysfunction due to spinal cordinjury, selective serotonin re-uptake inhibitor (SSRI) induced sexualdysfunction, premature labour, dysmenorrhoea, benign prostatichyperplasia (BPH), bladder outlet obstruction, incontinence, stable,unstable and variant (Prinzmetal) angina, hypertension, pulmonaryhypertension, chronic obstructive pulmonary disease, coronary arterydisease, congestive heart failure, atherosclerosis, conditions ofreduced blood vessel patency, peripheral vascular disease, stroke,nitrate induced tolerance, bronchitis, allergic asthma, chronic asthma,allergic rhinitis, diseases and conditions of the eye, diseasescharacterised by disorders of gut motility, pre-eclampsia, Kawasaki'ssyndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy,neuropathy including autonomic and peripheral neuropathy and inparticular diabetic neuropathy and symptoms thereof, Alzheimer'sdisease, acute respiratory failure, psoriasis, skin necrosis, cancer,metastasis, baldness, nutcracker oesophagus, anal fissure, haemorrhoids,hypoxic vasoconstriction or blood pressure stabilisation duringhaemodialysis. Particularly preferred conditions include MED and FSD.

[0391] Additionally, the invention provides a method of treating orpreventing a medical condition for which a cGMP PDE5 inhibitor isindicated, in a mammal (including a human being), which comprisesadministering to said mammal a therapeutically effective amount of acompound of formula (I), (IA) or (IB), or a female sexual dysfunction(FSD), clitoral dysfunction, female hypoactive sexual desire disorder,female sexual arousal disorder, female sexual pain disorder, femalesexual orgasmic dysfunction (FSOD), sexual dysfunction due to spinalcord injury, selective serotonin re-uptake inhibitor (SSRI) inducedsexual dysfunction, premature labour, dysmenorrhoea, benign prostatichyperplasia (BPH), bladder outlet obstruction, incontinence, stable,unstable and variant (Prinzmetal) angina, hypertension, pulmonaryhypertension, chronic obstructive pulmonary disease, coronary arterydisease, congestive heart failure, atherosclerosis, conditions ofreduced blood vessel patency, peripheral vascular disease, stroke,nitrate induced tolerance, bronchitis, allergic asthma, chronic asthma,allergic rhinitis, diseases and conditions of the eye, diseasescharacterised by disorders of gut motility, pre-eclampsia, Kawasaki'ssyndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy,neuropathy including autonomic and peripheral neuropathy and inparticular diabetic neuropathy and symptoms thereof e.g. gastroparesis,peripheral diabetic neuropathy, Alzheimer's disease, acute respiratoryfailure, psoriasis, skin necrosis, cancer, metastasis, baldness,nutcracker oesophagus, anal fissure, haemorrhoids, hypoxicvasoconstriction or blood pressure stabilisation of during haemodialysisin a mammal (including a human being).

[0392] The invention also includes any novel intermediates describedherein, for example those of formulae (IXA), (IXB), (VIIA), (VIIB),(VIII), (VIIIA) and (X). The present invention additionally comprisesthe combined administration of a cGMP PDE₅ inhibitor of the generalformula (1), wherein said combined administration can be in the form ofsimultaneous, sequential or joint administration with:

[0393] (a) one or more naturally occurring or synthetic prostaglandinsor esters thereof. Suitable prostaglandins for use herein includecompounds such as alprostadil, prostaglandin E₁, prostaglandin E₀, 13,14-dihydroprostaglandin E₁, prostaglandin E₂, eprostinol, naturalsynthetic and semi-synthetic prostaglandins and derivatives thereofincluding those described in U.S. Pat. No. 6,037,346 issued on 14th Mar.2000 and incorporated herein by reference, PGE₀, PGE₁, PGA₁, PGB₁, PGF₁α, 19-hydroxy PGA₁, 19-hydroxy-PGB₁, PGE₂, PGB₂, 19-hydroxy-PGA₂,19-hydroxy-PGB₂, PGE₃α, carboprost tromethamine dinoprost, tromethamine,dinoprostone, lipo prost, gemeprost, metenoprost, sulprostune, tiaprostand moxisylate; and/or

[0394] (b) one or more α-adrenergic receptor antagonist compounds alsoknown as α-adrenoceptors or α-receptors or α-blockers. Suitablecompounds for use herein include: the α-adrenergic receptors asdescribed in PCT application WO99/30697 published on 14th Jun. 1998, thedisclosures of which relating to α-adrenergic receptors are incorporatedherein by reference and include, selective α₁-adrenoceptors orα₂-adrenoceptors and non-selective adrenoceptors, suitableα₁-adrenoceptors include: phentolamine, phentolamine mesylate,trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole,phenoxybenzamine, idazoxan, efaraxan, yohimbine, rauwolfa alkaloids,Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin,terazosin, abanoquil and prazosin; a₂-blockers from U.S. Pat. No.6,037,346 [14th March-2000]-dibenamine, tolazoline, trimazosin anddibenamine; α-adrenergic receptors as described in U.S. Pat. Nos.4,188,390; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666;2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000 each of whichis incorporated herein by reference; α₂-Adrenoceptors include:clonidine, papaverine, papaverine hydrochloride, optionally in thepresence of a cariotonic agent such as pirxamine; and/or

[0395] (c) one or more NO-donor (NO-agonist) compounds. SuitableNO-donor compounds for use herein include organic nitrates, such asmono- di or tri-nitrates or organic nitrate esters including glycerylbrinitrate (also known as nitroglycerin), isosorbide 5-mononitrate,isosorbide dinitrate, pentaerythritol tetranitrate, erythrityltetranitrate, sodium nitroprusside (SNP), 3-morpholinosydnoniminemolsidomine, S-nitroso-N-acetyl penicilliamine (SNAP)S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, amyInitrate,linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso-N-cysteine,diazenium diolates, (NONOates), 1,5-pentanedinitrate, L-arginene,ginseng, zizphi fructus, molsidomine, Re-2047, nitrosylated maxisylytederivatives such as NMI-678-11 and NMI-937 as described in published PCTapplication WO 0012075; and/or

[0396] (d) one or more potassium channel openers. Suitable potassiumchannel openers for use herein include nicorandil, cromokalim,levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil,charybdotoxin, glyburide, 4-amini pyridine, BaCl₂; and/or

[0397] (e) one or more dopaminergic agents. Suitable dopaminergiccompounds for use herein include D₂-agonists such as, pramipexol;apomorphine; and/or

[0398] (f) one or more vasodilator agents. Suitable vasodilator agentsfor use herein include nimodepine, pinacidil, cyclandelate, isoxsuprine,chloroprumazine, halo peridol, Rec 15/2739, trazodone, pentoxifylline;and/or

[0399] (g) one or more thromboxane A2 agonists; and/or

[0400] (h) one or more CNS active agents; and/or

[0401] (i) one or more ergot alkoloids; Suitable ergot alkaloids aredescribed in U.S. Pat. No. 6,037,346 issued on 14th Mar. 2000 andinclude acetergamine, brazergoline, bromerguride, cianergoline,delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate,etisulergine, lergotrile, lysergide, mesulergine, metergoline,metergotamine, nicergoline, pergolide, propisergide, proterguride,terguride; and/or

[0402] (k) one or more compounds which modulate the action of atrialnatruretic factor (also known as atrial naturetic peptide), such asinhibitors or neutral endopeptidase; and/or

[0403] (l) one or more compounds which inhibit angiotensin-convertingenzyme such as enapril, and combined inhibitors ofangiotensin-converting enzyme and neutral endopeptidase such asomapatrilat; and/or

[0404] (m) one or more angiotensin receptor antagonists such aslosartan; and/or

[0405] (n) one or more substrates for NO-synthase, such as L-arginine;and/or

[0406] (o) one or more calcium channel blockers such as amlodipine;and/or

[0407] (p) one or more antagonists of endothelin receptors andinhibitors or endothelin-converting enzyme; and/or

[0408] (q) one or more cholesterol lowering agents such as statins andfibrates; and/or

[0409] (r) one or more antiplatelet and antithrombotic agents, e.g. tPA,uPA, warfarin, hirudin and other thrombin inhibitors, heparin,thromboplastin activating factor inhibitors; and/or

[0410] (s) one or more insulin sensitising agents such as rezulin andhypoglycaemic agents such as glipizide; and/or

[0411] (t) L-DOPA or carbidopa; and/or

[0412] (u) one or more acetylcholinesterase inhibitors such asdonezipil; and/or

[0413] (v) one or more steroidal or non-steroidal anti-inflammatoryagents.

[0414] The syntheses of the compounds of the invention and of theintermediates for use therein are illustrated by the following Examplesand Preparations. A number of the compounds included in the Preparationssection are compounds of the formula (I), (IA) or (IB) and are therebyexamples of compounds according to the present invention.

[0415]¹H Nuclear magnetic resonance (NMR) spectra were recorded usingeither a Varian Unity 300 or a Varian Inova 400 spectrometer and were inall cases consistent with the proposed structures. Characteristicchemical shifts (δ) are given in parts-per-million downfield fromtetramethylsilane using conventional abbreviations for designation ofmajor peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br, broad.

[0416] Mass spectra (m/z) were recorded using a Fisons Instruments Triomass spectrometer in the thermospray ionisation mode.

[0417] Room temperature means 20 to 25° C.

EXAMPLE 15-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-methoxyethyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0418]

[0419] A mixture of the title compound from preparation 28 (560 mg, 1.04mmol) and potassium tert-butoxide (292 mg, 2.4 mmol) in ethanol (20 ml)was heated at 100° C. in a sealed vessel for 18 hours. The cooledmixture was concentrated under reduced pressure and the residuepartitioned between ethyl acetate and water. The organic phase wasseparated, dried (MgSO₄) and evaporated under reduced pressure. Thecrude product was purified by column chromatography on silica gel usingan elution gradient of dichloromethane:methanol (100:0 to 95:5) toafford the title compound, 220 mg.

[0420] Found: C, 52.65; H, 6.43; N, 18.39. C₂₃H₃₃N₇O₅S; 0.3H₂O requiresC, 53.16; H, 6.40; N, 18.87%.

[0421] δ (CDCl₃): 1.02 (3H, t), 1.58 (3H, t), 1.84 (2H, m), 2.28 (3H,s), 2.52 (4H, m), 3.01 (2H, t), 3.15 (4H, m), 3.30 (3H, s), 3.90 (2H,t), 4.45 (2H, t), 4.77 (2H, q), 8.62 (1H, s), 9.02 (1H, s), 10.61 (1H,s).

[0422] LRMS: m/z 520 (M+1)⁺

EXAMPLE 25-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2.6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0423]

[0424] A mixture of the title compound from preparation 27 (420 mg, 0.80mmol) and potassium bis(trimethylsilyl)amide (240 mg, 1.20 mmol) inethanol (40 ml) was heated at 100° C. for 18 hours in a sealed vessel.The cooled mixture was concentrated under reduced pressure and theresidue purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (100:0 to 90:10) to give the titlecompound, 130 mg.

[0425] δ (CDCl₃): 1.40 (3H, t), 1.58 (3H, t), 2.27 (3H, s), 2.50 (4H,m), 3.10 (6H, m), 3.30 (3H, s), 3.92 (2H, t), 4.45 (2H, t), 4.75 (2H,q), 8.62 (1H, d), 9.02 (1H, d), 10.65 (1H, s).

[0426] LRMS: m/z 506 (M+1)⁺

EXAMPLE 35-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-methoxyethyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0427]

[0428] A mixture of the title compound from preparation 30 (740 mg, 1.34mmol) and potassium bis(trimethylsilyl)amide (321.5 mg, 1.61 mmol) inethanol (40 ml) was heated at 100° C. for 18 hours in a sealed vessel.Tlc analysis showed starting material remaining, so additional potassiumbis(trimethylsilyl)amide (321.5 mg, 1.61 mmol) was added, and thereaction continued for a further 18 hours. The cooled mixture wasconcentrated under reduced pressure and the residue partitioned betweenwater and ethyl acetate, and the layers separated. The organic phase wasevaporated under reduced pressure and the crude product was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane:methanol (100:0 to 90:10) to give the title compound,150 mg.

[0429] δ (CDCl₃): 1.02 (6H, m), 1.58 (3H, t), 1.83 (2H, m), 2.41 (2H,q), 2.56 (4H, m), 3.01 (2H, t), 3.14 (4H, m), 3.29 (3H, s), 3.90 (2H,t), 4.44 (2H, t), 4.75 (2H, q), 8.61 (1H, s), 9.02 (1H, s), 10.61 (1H,s).

[0430] LRMS: m/z 534 (M+1)⁺

EXAMPLE 42-(sec-Butyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0431]

[0432] A mixture of the title compound from preparation 39 (400 mg, 0.75mmol), potassium bis(trimethylsilyl)amide (298 mg, 1.50 mmol) and ethylacetate (73%1, 0.75 mmol) in ethanol (10 ml) was heated at 120° C. in asealed vessel for 12 hours. The cooled mixture was partitioned betweenethyl acetate and aqueous sodium bicarbonate solution, and the layersseparated. The organic phase was dried (MgSO₄), and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol (98:2) aseluant to afford the title compound, 164 mg.

[0433] δ (CDCl₃): 0.79 (3H, t), 1.02 (3H, t), 1.38 (3H, t), 1.56 (6H,m), 1.90 (1H, m), 2.21 (1H, m), 2.41 (2H, q), 2.57 (4H, m), 2.98-3.18(6H, m), 4.41 (1H, m), 4.75 (2H, q), 8.61 (1H, s), 9.02 (1H, s), 10.58(1H, s).

Examples 5 to 9

[0434] The compounds of the following tabulated examples, of generalstructure:

[0435] were prepared from the corresponding carboxamides, following asimilar procedure to that described in example 4. Yield Example R1 (%)Data 5

23 δ(CDCl₃): 0.97(6H, d), 1.02(3H, t), 1.40(3H, t), 1.58(3H, t),2.41(3H, m), 2.56(4H, m), 3.01(2H, q), 3.14(4H, m), 4.10(2H, d),4.75(2H, q), 8.61(1H, s), 9.02(1H, s), 10.61(1H, s). 6¹

28 δ(CDCl₃): 0.47(2H, m), 0.63(2H, m), 1.01(3H, t), 1.40(3H, t),1.48-1.72(4H, m), 2.45(2H, q), 2.56(4H, m), 3.04 (2H, q), 3.15(4H, m),3.47(2H, q), 4.20 (2H, d), 4.76(2H, q), 8.61(1H, s), 9.02 (1H, s),10.60(1H, s). LRMS: m/z 516(M + 1)⁺ 7¹

48 δ(CDCl₃): 1.01(3H, t), 1.20(3H, t), 1.40(3H, t), 1.56(4H, m),1.88(4H, m), 2.07(2H, m), 2.40(2H, q), 2.56(4H, m), 3.00(2H, m),3.15(4H, m), 4.34 (2H, d), 4.76(2H, q), 8.61(1H, s), 9.02 (1H, s),10.60(1H, s). LRMS: mz 530 (M + 1)⁺ 8²

27 Found: C, 53.18; H, 6.48; N, 18.14. C₂₃H₃₃N₇O₅S;0.20C₂H₅CO₂CH₃requires C, 53.21; H, 6.49; N, 18.25%. δ(CDCl₃): 1.04(3H,t), 1.40(3H, t), 1.58(3H, t), 2.41(2H, q), 2.57(4H, m), 3.08(2H, q),3.14(4H, m), 3.30(3H, s), 3.92(2H, t), 4.46 #(2H, t), 4.75(2H, q),8.62(1H, d), 9.04(1H, d), 10.61(1H, s). LRMS: m/z 520(M + 1)⁺mp 161-162°C. 9

47 δ(CDCl₃): 1.02(3H, t), 1.38(3H, t), 1.58(6H, m), 2.41(2H, q),2.57(4H, m), 3.05(2H, m), 3.14(4H, m), 3.22 (3H, s), 3.72(1H, m),3.96(1H, dd), 4.73(3H, m), 8.61(1H, s), 9.02(1H, s), 10.56(1H, s). LRMS:m/z 534(M + 1)⁺

EXAMPLE 105-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(tetrahydrofuran-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0436]

[0437] A mixture of the title compound from preparation 42 (250 mg, 0.44mmol), potassium bis(trimethylsilyl)amide (132 mg, 0.66 mmol) and ethylacetate (40%1, 0.41 mmol) in 3-methyl-3-pentanol (4 ml) was heated at120° C. in a sealed vessel for 18 hours. Tlc analysis showed startingmaterial remaining, so additional potassium bis(trimethylsilyl)amide(132 mg, 0.66 mmol) was added and the reaction heated under reflux for afurther 24 hours. The cooled mixture was evaporated under reducedpressure, and the residue purified by column chromatography on silicagel using an elution gradient of dichloromethane:methanol (100:0 to95:5) to give the title compound, 60 mg.

[0438] δ (CDCl₃): 1.03 (3H, t), 1.40 (3H, t), 1.58 (3H, t), 1.84 (3H,m), 2.08 (1H, m), 2.41 (2H, q), 2.56 (4H, m), 3.14 (6H, m), 3.70-3.90(2H, m), 4.30-4.50 (3H, m), 4.75 (2H, q), 8.62 (1H, s), 9.02 (1H, s),10.62 (1H, s).

[0439] LRMS: m/z 546 (M+1)⁺

EXAMPLE 115-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-(pyrazol-1-yl)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0440]

[0441] A mixture of the title compound from preparation 48 (300 mg, 0.52mmol), potassium bis(trimethylsilyl)amide (320 mg, 1.57 mmol) and ethylacetate (50 μl, 0.52 mmol) in ethanol (40 ml) was heated at 130° C. in asealed vessel for 18 hours. The cooled mixture was concentrated underreduced pressure and the residue partitioned between water anddichloromethane and the layers separated. The aqueous phase wasextracted with dichloromethane, and the combined organic solutions weredried (Na₂SO₄), and evaporated under reduced pressure. The crude productwas purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (100:0 to 90:10), and trituratedwith ethyl acetate to afford the title compound as a white solid, 80 mg.

[0442] δ (CDCl₃): 1.01 (3H, t), 1.18 (3H, t), 1.57 (3H, t), 2.41 (2H,q), 2.58 (6H, m), 3.14 (4H, m), 4.77 (6H, m), 6.08 (1H, m), 6.96 (1H,d), 7.57 (1H, d), 8.62 (1H, d), 9.00 (1H, d), 10.67 (1H, s).

[0443] LRMS: m/z 556 (M+1)⁺

EXAMPLE 125-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-(methylamino)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0444]

[0445] A mixture of the title compound of preparation 54 (130 mg, 0.24mmol) and potassium bis(trimethylsilyl)amide (58 mg, 0.29 mmol) inethanol (6 ml) was heated at 130° C. for 16 hours in a sealed vessel.The cooled mixture was concentrated under reduced pressure, the residuesuspended in sodium bicarbonate solution (15 ml) and extracted withethyl acetate (3×15 ml). The combined organic extracts were dried(MgSO₄) and evaporated under reduced pressure. The residual gum waspurified by column chromatography on silica gel twice, usingdichloromethane:methanol:0.88 ammonia (89:10:1) as eluant and repeatedusing ethyl acetate:methanol:diethylamine. (78:20:2) as eluant to affordthe title compound, 32 mg, as a beige foam.

[0446] δ (CDCl₃): 1.02 (3H, t), 1.41 (3H, t), 1.58 (3H, t), 2.41 (2H,q), 2.56 (7H, m), 3.10 (6H, m), 3.27 (2H, t), 4.47 (2H, t), 4.77 (2H,q), 8.61 (1H, s), 9.00 (1H, s), 10.50-10.80 (1H, br s).

[0447] LRMS: m/z 519 (M+1)⁺

EXAMPLES 13 TO 15

[0448] The following tabulated examples of the general structure:

[0449] were prepared from the corresponding carboxamides, following asimilar procedure to that described in example 12. Yield Example R1 (%)¹Hnmr 13¹

81 δ(CDCl₃): 1.02(3H, t), 1.42(3H, t), 1.58 3H, t), 2.30(6H, s),2.41(2H, q), 2.56(4H, m), 2.90(2H, t), 3.05(2H, q), 3.14(4H, m),4.40(2H, t), 4.75(2H, q), 8.61(1H, s), 9.02(1H, s), 10.62(1H, s). 14¹

21 δ(CDCl₃): 1.03(3H, t), 1.40(3H, t), 1.44(9H, s), 1.58(3H, t),2.41(2H, q), 2.54-2.68(7H, m), 3.01(2H, q), 3.16 (4H, m), 3.78(2H, t),4.47(2H, m), 4.78 (2H, q), 8.63(1H, s), 9.04(1H, s), 10.66(1H, br s).15¹

58 δ(CDCl₃): 1.02(3H, t), 1.40(3H, t), 1.58(3H, t), 1.93(2H, m),2.16(2H, m), 2.36(3H, s), 2.41(2H, q), 2.56(6H, m), 3.04(4H, m),3.14(4H, m), 4.22(1H, m), 4.77(2H, q), 8.62(1H, d), 9.01(1H, d),10.54(1H, s).

EXAMPLE 165-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0450]

[0451] A mixture of the title compound from preparation 53 (470 mg, 0.86mmol) and potassium bis(trimethylsilyl)amide (600 mg, 3.0 mmol) inethanol (45 ml) was heated at 130° C. for 16 hours. The cooled mixturewas concentrated under reduced pressure, the solution diluted withaqueous sodium bicarbonate solution to give pH 8, and extracted withethyl acetate (3×). The combined organic extracts were dried (MgSO₄) andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using dichloromethane:methanol:0.88ammonia (91.75:7.5:0.75) as eluant to give the title compound, 170 mg.

[0452] δ (CDCl₃): 1.02 (3H, t), 1.38 (3H, t), 1.58 (3H, m), 2.40 (2H,q), 2.50 (3H, s), 2.57 (4H, m), 3.01 (2H, q), 3.16 (4H, m), 3.79 (2H,t), 3.90 (2H, t), 4.78 (2H, q), 5.12 (1H, m), 8.62 (1H, d), 9.01 (1H,d), 10.62 (1H, s).

EXAMPLE 175-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-dimethylaminoethyl-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0453]

[0454] A mixture of the title compound from preparation 55 (150 mg, 0.27mmol) and potassium bis(trimethylsilyl)amide (109 mg, 0.55 mmol) inn-butanol (5 ml) was heated at 120° C. for 16 hours in a sealed vessel.The cooled reaction mixture was poured into saturated aqueous sodiumbicarbonate solution, and extracted with ethyl acetate. The combinedorganic extracts were dried (MgSO₄), and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using dichloromethane:methanol (90:10) as eluant to affordthe title compound as a white foam, 27 mg.

[0455] δ (CDCl₃): 1.02 (6H, m), 1.42 (3H, t), 1.57 (2H, m), 1.95 (2H,m), 2.30 (6H, s), 2.41 (2H, q), 2.57 (4H, m), 2.90 (2H, t), 3.05 (2H,q), 3.16 (4H, m), 4.40 (2H, t), 4.66 (2H, t), 8.61 (1H, d), 9.01 (1H,t), 10.60 (1H, s).

EXAMPLE 182-(Azetidin-3-yl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneditrifluoroacetate

[0456]

[0457] Trifluoroacetic acid (3 ml) was added to a solution of the titlecompound from preparation 63 (350 mg, 0.57 mmol) in dichloromethane (3ml), and the reaction stirred at room temperature for 2½ hours. Thereaction was concentrated under reduced pressure and the residual gumwas triturated several times with ether. The resulting suspension wassonicated for a minute, then the solid filtered, washed with ether, anddried to give the title compound as a white powder, 280 mg.

[0458] Found: C, 42.82; H, 4.80; N, 14.92. C₂₃H₃₂N₈O₄S; 2CF₃CO₂H; H₂Orequires C, 42.52; H, 4.76; N, 14.69%.

[0459] δ (DMSOd₆): 1.14 (3H, m), 1.21 (3H, t), 1.34 (3H, t), 2.70-3.44(12H, m), 4.47 (6H, m), 5.68 (1H, m), 8.24 (1H, s), 8.74 (1H, s),9.14-9.30 (2H, m), 12.02 (1H, s).

EXAMPLE 192-(Azetidin-3-yl)-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(1-methylbutoxy)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneDitrifluoroacetate

[0460]

[0461] The title compound was obtained as a beige-coloured powder,(51%), from the title compound of preparation 66, following a similarprocedure to that described in example 18.

[0462] δ (DMSOd₆): 0.86 (3H, t), 1.07-1.46 (12H, m), 2.41-3.50 (12H, m),4.49 (4H, m), 5.38 (1H, m), 5.68 (1H, m), 8.26 (1H, s), 8.74 (1H, s),9.00 (1H, m), 9.26 (1H, m), 11.96 (1H, s).

EXAMPLE 205-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-n-propoxypyridin-3-yl]-3-ethyl-2-[2-(methylamino)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneDitrifluoroacetate

[0463]

[0464] The title compound was obtained as a white solid, (79%) from thetitle compound from preparation 61 and trifluoroacetic acid, followingthe procedure described in example 18.

[0465] δ (DMSOd₆): 0.94 (3H, t), 1.12 (3H, m), 1.26 (3H, t), 1.73 (2H,m), 2.41 (6H, m), 2.60 (3H, s), 2.68-3.60 (7H, m), 4.39 (2H, t), 4.60(2H, t), 8.23 (1H, s), 8.57 (2H, m), 8.74 (1H, s), 11.94 (1H, s).

EXAMPLE 215-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0466]

[0467] Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added to asolution of the title compound from example 18 (215 mg, 0.28 mmol),acetaldehyde (17.3 μl, 0.31 mmol), acetic acid (16 μl, 0.28 mmol) andtriethylamine (7.9 μl, 0.28 mmol) in tetrahydrofuran (6 ml), and thereaction stirred at room temperature for 16 hours. The reaction mixturewas diluted with saturated aqueous sodium bicarbonate solution (30 ml),and this mixture extracted with ethyl acetate (2×30 ml). The combinedorganic extracts were-dried (MgSO₄), and evaporated under reducedpressure. The residual gum was purified by column chromatography onsilica gel using dichloromethane:methanol (90:10) as eluant, to give thetitle compound, 120 mg.

[0468] δ (CDCl₃): 1.04 (6H, m), 1.38 (3H, t), 1.58 (3H, t), 2.41 (2H,q), 2.57 (4H, m), 2.68 (2H, q), 3.01 (2H, q), 3.15 (4H, m), 3.76 (2H,m), 3.95 (2H, m), 4.76 (2H, q), 5.16 (1H, m), 8.63 (1H, d), 9.02 (1H,d), 10.68 (1H, s).

EXAMPLE 222-(1-Acetylazetidin-3-yl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0469]

[0470] Acetyl chloride (6 mg, 0.076 mmol) was added to a mixture of thetitle compound from example 18 (43 mg, 0.056 mmol) and triethylamine(8.5 mg, 0.086 mmol) in dichloromethane (2 ml), and the reaction stirredfor 36 hours at room temperature. The mixture was treated with aqueoussaturated sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic extracts were dried (MgSO₄), and evaporatedunder reduced pressure. The residual gum was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol (97:3 to 95:5) to give the title compound, 19mg.

[0471] δ (CDCl₃): 1.02 (3H, t), 1.38 (3H, t), 1.60 (3H, t), 1.98 (3H,s), 2.42 (2H, q), 2.58 (4H, m), 3.02 (2H, q), 3.16 (4H, m), 4.50 (2H,m), 4.59 (1H, m), 4.78 (2H, q), 5.05 (1H, m), 5.31 (1H, m), 8.62 (1H,d), 9.01 (1H, d), 10.70 (1H, s).

EXAMPLE 232-(1-Acetylpiperidin-4-yl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0472]

[0473] The title compound was obtained (30%) from the compound ofpreparation 68, and acetyl chloride, following the procedure describedin example 22.

[0474] δ (CDCl₃): 1.02 (3H, t), 1.40 (3H, t), 1.56 (3H, t), 2.00 (2H,m), 2.17 (3H, s), 2.23-2.44 (4H, m), 2.55 (4H, m), 2.78 (1H, m), 3.09(6H, m), 3.27 (1H, m), 4.06 (1H, m), 4.50 (1H, m), 4.70-4.90 (3H, m),8.62 (1H, d), 9.02 (1H, d), 10.60 (1H, s).

EXAMPLE 242-[2-[Acetyl(methyl)amino]ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxypyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0475]

[0476] The title compound was obtained (74%) from the compound ofexample 20, and acetyl chloride, following the procedure described inexample 22.

[0477] δ (CDCl₃): 1.02 (3H, t), 1.14 (3H, t), 1.40 (3H, t), 1.99 (2H,m), 2.06 (3H, s), 2.42 (2H, q), 2.57 (4H, m), 2.80 (3H, s), 3.01 (2H,q), 3.16 (4H, m), 3.93 (2H, t), 4.50 (2H, t), 4.62 (2H, t), 8.62 (1H,d), 9.04 (1H, d), 10.66 (1H, s).

EXAMPLE 255-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[1-(methylsulphonyl)piperidin-4-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0478]

[0479] The title compound was obtained (33%) from the title compoundfrom preparation 68 and methanesulphonic anhydride, following a similarprocedure to that described in example 22.

[0480] δ (CDCl₃): 1.02 (3H, t), 1.40 (3H, t), 1.58 (3H, t), 2.10 (2H,m), 2.40 (2H, q), 2.56 (6H, m), 2.90 (3H, s), 3.00-3.20 (8H, m), 4.01(2H, m), 4.21 (1H, m), 4.78 (2H, q), 8.62 (1H, d), 9.01 (1H, s), 10.61(1H, s).

EXAMPLE 262-(1-Acetylazetidin-3-yl)-5-[2-n-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0481]

[0482] Trifluoroacetic acid (0.5 ml) was added to a solution of thetitle compound from preparation 65 (28 mg, 0.043 mmol) indichloromethane (0.5 ml), and the solution stirred for 2½ hours at roomtemperature. The mixture was evaporated under reduced pressure and theresidue triturated with ether several times. The resulting precipitatewas filtered off, washed with ether and dried, to give a beige-colouredsolid.

[0483] Acetyl chloride (16 μl, 0.22 mmol) was added to a solution ofthis intermediate in dichloromethane (3 ml) and triethylamine (61 μl,0.44 mmol), and the reaction stirred at room temperature for 16 hours.Aqueous saturated sodium bicarbonate solution (10 ml) was added, and themixture extracted with ethyl acetate. The combined organic extracts weredried (MgSO₄) and evaporated under reduced pressure to give a gum. Thecrude product was purified by column chromatography on silica gel usingan elution gradient of dichloromethane:methanol (98:2 to 95:5) to givethe title compound, 7 mg.

[0484] δ (CDCl₃): 1.02 (6H, m), 1.38 (3H, t), 1.57 (2H, m), 1.94 (5H,m), 2.40 (2H, q), 2.47 (4H, m), 3.02 (2H, q), 3.14 (4H, m), 4.50 (2H,m), 4.59 (1H, m), 4.67 (2H, m), 5.06 (1H, m), 5.31 (1H, m), 8.62 (1H,d), 9.01 (1H, d), 10.68 (1H, s).

EXAMPLE 275-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0485]

[0486] Potassium bis(trimethylsilyl)amide (149.7 mg, 0.75 mmol) wasadded to a solution of the title compound of example 3 (80 mg, 0.15mmol) in 2-methyl-n-propanol (5 ml) and the reaction stirred at 120° C.for 18 hours. The cooled mixture was concentrated under reduced pressureand the residue suspended in water (10 ml), and extracted with ethylacetate (3×10 ml). The combined organic extracts were dried (MgSO₄) andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel, using an elution gradient ofdichloromethane:methanol (100:0 to 95:5) to afford the title compound,67 mg, as a solid.

[0487] Found: C, 54.92; H, 7.08; N, 16.92. C₂₆H₃₉N₇O₅S; 0.7H₂O requiresC, 54.38; H, 7.09; N, 17.07%

[0488] δ (CDCl₃): 1.03 (6H, m), 1.14 (6H, d), 1.83 (2H, m), 2.30 (1H,m), 2.41 (2H, q), 2.55 (4H, m), 3.01 (2H, t), 3.13 (4H, m), 3.30 (3H,s), 3.90 (2H, t), 4.46 (4H, m), 8.61 (1H, s), 9.01 (1H, s), 10.60 (1H,s).

[0489] LRMS: m/z 562 (M+1)⁺

EXAMPLES 28 TO 33

[0490] The compounds of the following tabulated examples of generalformula:

[0491] were prepared from the appropriate2-ethoxypyridin-3-ylpyrazolo[4,3-d]pyrimidinone and alcohol, followingsimilar procedures to that described in example 27. Ex R₁ R₃ Data 28

Found: C, 54.88; H, 7.08; N, 17.13, C₂₆H₃₉N₇O₅S; 0.6H₂O requires C,54.55; H, 7.08; N, 17.13% δ(CDCl₃): 1.02(6H, 2xt), 1.40(3H, t), 1.56(2H,m), 1.83(2H, m), 1.94(2H, m), 2.41(2H, q), 2.55(4H, m), 3.00(2H, t),3.16(4H, m), 3.30(3H, s), 3.92(2H, t), 4.45(2H, t), 4.67(2H, t),8.61(1H, s), 9.01(1H, s), 10.60(1H, s). LRMS: #m/z 562(M + 1)⁺ 29

Found: C, 52.90; H, 6.79; N, 16.86, C₂₅H₃₇N₇O₆S requires C, 53.27; H,6.62; N, 17.36% δ(CDCl₃): 1.02(6H, m), 1.84(2H, m), 2.42(2H, q),2.56(4H, m), 3.01(2H, t), 3.15(4H, m), 3.29(3H, s), 3.57(3H, s),3.88(4H, m), 4.44(2H, t), 4.78(2H, t), 8.61(1H, s), 8.98(1H, s),10.76(1H, s). LRMS: m/z 564 (M + 1)⁺ 30

n-Bu δ(CDCl₃): 1.02(6H, t), 1.38(3H, t), 1.57(2H, m), 1.96 (2H, m),2.41(2H, q), 2.50(3H, s), 2.56(4H, m), 3.00 (2H, q), 3.15(4H, m),3.79(2H, t), 3.94(2H, t), 4.68 (2H, t), 5.12(1H, m), 8.62(1H, d),9.01(1H, d), 10.61 (1H, s). 31

δ(CDCl₃): 1.01(3H, t), 1.37(3H, t), 2.40(2H, q), 2.55 (7H, m), 3.00(2H,q), 3.13(4H, m), 3.25(2H, t), 3.80 (2H, t), 3.95(2H, t), 4.88(2H, t),5.12(1H, m), 7.22 (2H, m), 7.38(3H, m), 8.62(1H, d), 9.00(1H, d), 10.49(1H, s). 32

n-Bu δ(CDCl₃): 1.02(9H, t), 1.38(3H, t), 1.57(2H, m), 1.96 (2H, m),2.41(2H, q), 2.56(4H, m), 2.67(2H, q), 3.01 (2H, q), 3.15(4H, m),3.74(2H, t), 3.90(2H, t), 4.68 (2H, t), 5.17(1H, m), 8.62(1H, d),9.01(1H, d), 10.60 (1H, s). 33

δ(CDCl₃): 1.02(6H, m), 1.37(3H, t), 2.41(2H, q), 2.57 (4H, m), 2.69(2H,q), 3.01(2H, q), 3.15(4H, m), 3.76 (2H, t), 3.95(2H, t), 5.18(1H, m),5.77(2H, s), 7.38 (3H, m), 7.50(2H, m), 8.63(1H, d), 9.00(1H, d), 10.59(1H, br s).

[0492] wherein for examples 28 and 29 R2 is n-propyl and for examples 30to 33 R2 is ethyl.

EXAMPLE 345-[2-iso-Butoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0493]

[0494] Potassium bis(trimethylsilyl)amide (306 mg, 1.54 mmol) was addedto a solution of the title compound of example 2 (155 mg, 0.31 mmol) in2-methyl-n-propanol (10 ml) and the reaction stirred under reflux for 24hours. The cooled mixture was evaporated under reduced pressure and theresidue purified by column chromatography on silica gel, using anelution gradient of dichloromethane:methanol (100:0 to 95:5) to affordthe title compound, 88 mg, as a solid.

[0495] Found: C, 52.45; H, 6.43; N, 17.33. C₂₄H₃₅N₇O₅S; 1.1H₂O requiresC, 52.08; H, 6.77; N, 17.71%

[0496] δ (CDCl₃): 1.14 (6H, d), 1.41 (3H, t), 2.30 (4H, m), 2.52 (4H,m), 3.07 (2H, q), 3.15 (4H, m), 3.30 (3H, s), 3.92 (2H, t), 4.46 (4H,m), 8.62 (1H, s), 9.03 (1H, s).

[0497] LRMS: m/z 534 (M+1)⁺

EXAMPLES 35 TO 40

[0498] The compounds of the following tabulated examples of the generalformula:

[0499] were prepared from the title compound of example 8 and theappropriate alcohol, following similar procedures to that described inexample 34. Ex R3 Data 35

δ(CDCl₃): 1.02(3H, t), 1.40(3H, t), 1.52(3H, t), 1.98 (2H, m), 2.40(2H,q), 2.57(4H, m), 3.14(6H, m), 3.32 (3H, s), 3.94(2H, t), 4.46(2H, t),4.62(2H, t), 8.61(1H, s), 9.02(1H, s), 10.62(1H, s). LRMS: m/z 534(M +1)⁺ 36

δ(CDCl₃): 1.04(6H, 2xt), 1.40(3H, t), 1.55(2H, m), 1.95(2H, m), 2.42(2H,q), 2.55(4H, m), 3.07(2H, q), 3.15(4H, m), 3.30(3H, s), 3.92(2H, t),4.46(2H, t), 4.66 (2H, t), 8.62(1H, s), 9.02(1H, s), 10.60(1H, s). LRMS:m/z 548(M + 1)⁺ 37

Found: C, 54.77; H, 6.82; N, 17.75. C₂₅H₃₇N₇O₅S requires C, 54.83; H,6.81; N, 17.90% δ(CDCl₃): 1.02(3H, t), 1.12(6H, d), 1.40(3H, t), 2.30(1H, m), 2.42(2H, q), 2.57(4H, m), 3.08(2H, q), 3.13 (4H, m), 3.30(3H,s), 3.90(2H, t), 4.46(4H, m). 8.62 (1H, s), 9.02(1H, s), 10.60(1H, s).LRMS: #m/z 548(M + 1)⁺ 38¹

Found: C, 54.76; H, 6.79; N, 17.72. C₂₅H₃₇N₇O₅S requires C, 54.83; H,6.81; N, 17.90% δ(CDCl₃): 1.03(6H, m), 1.40(3H, t), 1.50(3H, d), 1.85(1H, m), 1.98(1H, m), 2.41(2H, q), 2.58(4H, m), 3.07 2H, q), 3.15(4H,m), 3.30(3H, s), #3.92(2H, t), 4.47 (2H, t), 5.57(1H, m), 8.61(1H, s),9.03(1H, s), 10.65 (1H, s). LRMS: m/z 548(M + 1)⁺ 39¹

Found: C, 55.03; H, 6.97; N, 16.84. C₂₅H₃₇N₇O₅S requires C, 54.83; H,6.81; N, 17.90% δ(CDCl₃): 1.04(6H, t), 1.40(3H, t), 1.50(3H, d), 1.83(1H, m), 1.98(1H, m), 2.42(2H, q), 2.58(4H, m), 3.07 (2H, q), 3.15(4H,m), 3.30(3H, s), 3.92(2H, t), 4.46 (2H, t), 5.55(1H, m), 8.61(1H, s),9.04(1H, s), #10.64 (1H, s). LRMS: m/z 548(M + 1)⁺ 40

Found: C, 54.91; H, 5.91; N, 18.85. C₂₇H₃₄N₈O₅S; 0.5H₂O requires C,54.81; H, 5.96; N, 18.94% δ(CDCl₃): 1.02(3H, t), 1.42(3H, t), 2.42(2H,q), 2.57 (4H, m), 3.12(6H, m), 3.30(3H, s), 3.94(2H, t), 4.46 (2H, t),5.90(2H, s), 7.35(2H, m), 7.78(1H, m), 8.59 (1H, s), 8.84(2H, m),12.70(1H, s). LRMS: #m/z 583(M + 1)⁺

EXAMPLE 412-(sec-Butyl)-3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0500]

[0501] A solution of the title compound from example 4 (129 mg, 0.25mmol) in 2-methoxyethanol (10 ml) was heated at 110° C. for 15 minutes,then cooled. Potassium bis(trimethylsilyl)amide (249 mg, 1.50 mmol) wasadded and the reaction stirred at 130° C. for 22 hours. The cooledmixture was partitioned between ethyl acetate and aqueous sodiumbicarbonate solution, and the layers separated. The organic phase wasdried (MgSO₄) and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel usingdichloromethane:methanol (98:2) as eluant to afford the title compoundas a yellow foam, 59 mg.

[0502] δ (CDCl₃): 0.79 (3H, t), 1.03 (3H, t), 1.39 (3H, t), 1.60 (3H,d), 1.90 (1H, m), 2.22 (1H, m), 2.41 (2H, q), 2.57 (4H, m), 2.97-3.18(6H, m), 3.57 (3H, s), 3.85 (2H, m), 4.40 (1H, m), 4.78 (2H, m), 8.62(1H, s), 8.98 (1H, s), 10.76 (1H, s).

[0503] LRMS: m/z 548 (M+1)⁺

EXAMPLE 422-Cyclobutylmethyl-3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2.6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0504]

[0505] The title compound was obtained as a white solid (64%) from thetitle compound from example 7 and 2-methoxyethanol, following theprocedure described in example 41.

[0506] δ (CDCl₃): 1.01 (3H, t), 1.40 (3H, t), 1.80-1.98 (5H, m), 2.05(2H, m), 2.40 (2H, q), 2.54 (4H, m), 3.00 (2H, m), 3.15 (4H, m), 3.55(3H, s), 3.83 (2H, t), 4.30 (2H, d), 4.76 (2H, t), 8.60 (1H, s), 8.96(1H, d), 10.74 (1H, br s).

EXAMPLE 433-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(2-methoxy-1-methylethyl)-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0507]

[0508] The title compound was obtained as a yellow foam (57%) from thetitle compound from example 9 and 2-methoxyethanol, following theprocedure described in example 41.

[0509] δ (CDCl₃): 1.02 (3H, t), 1.38 (3H, t), 1.59 (3H, d), 2.41 (2H,q), 2.56 (4H, m), 3.05 (6H, m), 3.22 (3H, s), 3.56 (3H, s), 3.72 (1H,m), 3.84 (2H, m), 3.96 (1H, dd), 4.71 (1H, m), 4.78 (2H, m), 8.61 (1H,s), 8.97 (1H, s), 10.78 (1H, br s).

EXAMPLE 443-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1-methylethoxy)sulphonyl)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneand EXAMPLE 453-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1-methylethoxy)sulphonyl)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0510]

[0511] A mixture of the title compound from example 8 (250 mg, 0.48mmol) and potassium bis(trimethylsilyl)amide (480 mg, 2.41 mmol) in1-methoxy-2-propanol (20 ml) was heated at 120° C. for 18 hours. Thecooled mixture was evaporated under reduced pressure and the residuepurified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (100:0 to 95:5) to give a whitesolid. This material was purified by HPLC, using a Chiralpak AD 250column, with hexane: 1% diethylamine in isopropanol (85:15) as eluant,to give the title compound of example 44, 49 mg,

[0512] δ (CDCl₃): 1.02 (3H, t), 1.40 (3H, t), 1.50 (3H, m), 2.42 (2H,q), 2.57 (4H, m), 3.06 (2H, m), 3.15 (4H, m), 3.30 (3H, s), 3.55 (3H,s), 3.64 (1H, m), 3.76 (1H, m), 3.92 (2H, t), 4.45 (2H, t), 5.60 (1H,m), 8.60 (1H, s), 8.90 (1H, s), 10.80 (1H, s).

[0513] LRMS: m/z 564 (M+1)⁺

[0514] and the title compound of example 45, 39 mg.

[0515] δ (CDCl₃): 1.04 (3H, t), 1.40 (3H, t), 1.50 (3H, d), 2.42 (2H,q), 2.57 (4H, m), 3.07 (2H, q), 3.16 (4H, m), 3.29 (3H, s), 3.56 (3H,s), 3.64 (1H, m), 3.75 (1H, m), 3.90 (2H, t), 4.45 (2H, t), 5.60 (1H,m), 8.60 (1H, s), 8.90 (1H, s), 10.80 (1H, s).

[0516] LRMS: m/z 564 (M+1)⁺

EXAMPLE 465-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1-methylethoxy)sulphonyl)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneand EXAMPLE 475-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1-methylethoxy)sulphonyl)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0517]

[0518] A mixture of the title compound from example 3 (345 mg, 0.65mmol) and potassium bis(trimethylsilyl)amide (645 mg, 3.24 mmol) in1-methoxy-2-propanol (2.5 ml) was heated at 110° C. for 16 hours. Thecooled mixture was diluted with ethyl acetate, then washed with aqueousammonium chloride solution, then water, dried (MgSO₄), and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using dichloromethane:methanol (97:3) aseluant to give a yellow gum.

[0519] This material was purified by HPLC, using a Chiralpak AD 250column, with hexane:1% diethylamine in iso-propanol (85:15) as eluant,to give the title compound of example 46, 17 mg,

[0520] δ (CDCl₃): 1.02 (6H, m), 1.50 (3H, d), 1.81 (2H, m), 2.41 (2H,q), 2.56 (4H, m), 3.00 (2H, m), 3.14 (4H, m), 3.28 (3H, s), 3.55 (3H,s), 3.62-3.78 (2H, m), 3.90 (2H, t), 4.44 (2H, t), 5.60 (1H, m), 8.60(1H, s), 8.89 (1H, s), 10.80 (1H, s).

[0521] LRMS: m/z 578 (M+1)+

[0522] and the title compound of example 47, 64 mg.

[0523] δ (CDCl₃): 1.01 (6H, m), 1.48 (3H, d), 1.81 (2H, m), 2.40 (2H,q), 2.54 (4H, m), 2.99 (2H, t), 3.10 (4H, m), 3.27 (3H, s), 3.51 (3H,s), 3.60-3.76 (2H, m), 4.87 (2H, t), 4.44 (2H, t), 5.59 (1H, m), 8.60(1H, s), 8.86 (1H, s).

[0524] LRMS: m/z 578 (M+1)⁺

EXAMPLE 483-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-hydroxyethyl)-2.6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-oneand EXAMPLE 495-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-hydroxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0525]

[0526] Potassium bis(trimethylsilyl)amide (200 mg, 1.0 mmol) was addedto a solution of the title compound from preparation 60 (120 mg, 0.2mmol) in 1-methoxy-2-propanol (10 ml), and the reaction heated underreflux for 18 hours. The cooled mixture was evaporated under reducedpressure and the residue purified by column chromatography on silica gelusing an elution gradient of dichloromethane:methanol (100:0 to 90:10)to give the title compound of example 48, 8 mg.

[0527] δ (CDCl₃) 1.02 (3H, t), 1.40 (3H, t), 1.50 (3H, d), 2.41 (2H, q),2.58 (4H, m), 3.10 (7H, m), 3.58 (3H, s), 3.70 (2H, m), 4.20 (2H, m),4.40 (2H, m), 5.59 (1H, m), 8.61 (1H, d), 8.88 (1H, d), 10.90 (1H, s).

[0528] LRMS: m/z 550 (M+1)⁺

[0529] and the title compound of example 49 as a white solid.

[0530] δ (CDCl₃): 1.02 (3H, t), 1.40 (3H, t), 1.58 (3H, t), 2.41 (2H,q), 2.56 (4H, m), 2.87 (1H, br s), 3.02-3.19 (6H, m), 4.22 (2H, m), 4.42(2H, t), 4.77 (2H, q), 8.62 (1H, s), 9.02 (1H, s), 10.66 (1H, s).

[0531] LRMS: m/z 506 (M+1)⁺

EXAMPLE 502-(2-Ethoxyethyl)-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-3-ethyl-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0532]

[0533] Potassium bis(trimethylsilyl)amide (359 mg, 1.8 mmol) was addedto a solution of the title compound from preparation 70 (250 mg, 0.45mmol) in 2-methoxyethanol (5 ml), and the reaction heated under refluxfor 6 hours. Tlc analysis showed starting material remaining, soadditional potassium bis(trimethylsilyl)amide (90 mg, 0.45 mmol) wasadded to the cooled mixture, and the reaction stirred for a further 4hours under reflux. The cooled mixture was concentrated under reducedpressure and the residue purified by column chromatography on silica gelusing dichloromethane:methanol (95:5) as eluant. The product wastriturated with ether and pentane to afford the title compound as acrystalline solid, 75 mg. Found: C, 52.88; H, 6.59; N, 17.39.C₂₅H₃₇N₇O₆S requires C, 53.27; H, 6.62; N, 17.39%

[0534] d (CDCl₃): 1.02 (3H, t), 1.12 (3H, t), 1.40 (3H, t), 2.41 (2H,q), 2.57 (5H, m), 3.06 (2H, q), 3.15 (4H, m), 3.42 (2H, q), 3.57 (3H,s), 3.85 (2H, t), 3.94 (2H, t), 4.44 (2H, t), 4.78 (2H, t), 8.61 (1H,s), 8.98 (1H, s), 10.78 (1H, s).

EXAMPLE 512-(iso-Butyl)-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0535]

[0536] Potassium bis(trimethylsilyl)amide (732 mg, 3.68 mmol) was addedto a solution of the title compound from preparation 40 (958 mg, 1.84mmol) in 2-methoxyethanol (20 ml) and the reaction stirred for 16 hoursat 120° C. The cooled mixture was concentrated under reduced pressure,the residue dissolved in water (25 ml) and the pH adjusted to 2 usinghydrochloric acid (2N). The solution was washed with ethyl acetate,neutralised and the resulting precipitate filtered off. The solid wasdissolved in ethyl acetate, evaporated under reduced pressure and thecrude product was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant to give thetitle compound, 53 mg.

[0537] δ (CDCl₃): 0.97 (6H, d), 1.40 (3H, t), 2.28 (4H, m), 2.52 (4H,m), 3.02 (2H, q), 3.16 (4H, m), 3.57 (3H, s), 3.86 (2H, t), 4.10 (2H,d), 4.78 (2H, t), 8.61 (1H, d) 8.98 (1H, d), 10.79 (1H, s).

[0538] LRMS: m/z 534 (M+1)⁺

EXAMPLE 522-(iso-Butyl)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2.6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0539]

[0540] Potassium bis(trimethylsilyl)amide (1.85 g, 9.35 mmol) was addedto a solution of the title compound from preparation 36 (1.0 g, 1.89mmol) in 2-methoxyethanol (8 ml) and the reaction stirred for 18 hoursat 120° C. The cooled mixture was concentrated under reduced pressure,and the residue partitioned between water (200 ml) and dichloromethane(200 ml). The resulting precipitate was filtered off, and the layersseparated. The aqueous phase was extracted with dichloromethane (2×200ml), and the combined organic solutions evaporated under reducedpressure, to give a cream solid. The isolated solids were combined andpurified by column chromatography on silica gel usingdichloromethane:methanol (90:10) as eluant to give the title compound asa pale yellow solid, 220 mg.

[0541] δ (CDCl₃): 0.95 (6H, d), 1.05 (3H, t), 1.40 (3H, d), 2.40 (3H,m), 2.55 (4H, m), 3.00 (2H, q), 3.10 (4H, m), 3.55 (3H, s), 3.85 (2H,t), 5.05 (2H, d), 4.80 (2H, t), 8.60 (1H, s), 8.95 (1H, s), 10.80 (1H,s).

[0542] LRMS: m/z 549 (M+1)⁺

EXAMPLE 532-Cyclobutylmethyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0543]

[0544] The title compound was obtained as a beige solid (31%) from thetitle compound from preparation 41 and 2-methoxyethanol, using a similarprocedure to that described 52.

[0545] δ (CDCl₃): 1.41 (3H, t), 1.88 (4H, m), 2.07 (2H, m), 2.26 (3H,s), 2.52 (4H, m), 3.00 (3H, m), 3.15 (4H, m), 3.57 (3H, s), 3.86 (2H,m), 4.33 (2H, d), 4.79 (2H, t), 8.62 (1H, s), 8.98 (1H, s), 10.75 (1H,s).

EXAMPLE 545-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0546]

[0547] A mixture of the title compound from preparation 52 (90 mg, 0.156mmol), potassium bis(trimethylsilyl)amide (156 mg, 0.78 mmol) and ethylacetate (14 mg, 0.156 mmol) in iso-propanol (12 ml) was stirred at 130°C. for 6 hours in a sealed vessel. The cooled reaction mixture waspoured into saturated aqueous sodium bicarbonate solution (60 ml), andextracted with ethyl acetate (60 ml). The combined organic extracts weredried (MgSO₄), and evaporated under reduced pressure to give a gum. Thecrude product was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (92.6:6.6:0.6) to afford the titlecompound as a beige foam, 36 mg.

[0548] δ (CDCl₃): 1.01 (3H, t), 1.12 (6H, d), 1.39 (3H, t), 1.94 (2H,m), 2.15 (2H, m), 2.22-2.44 (6H, m), 2.55 (6H, m), 3.02 (4H, m), 3.14(4H, m), 4.22 (1H, m), 4.43 (2H, d), 8.60 (1H, d), 9.00 (1H, d), 10.54(1H, s).

EXAMPLES 55 TO 58

[0549] The compounds of the following tabulated examples of generalformula:

[0550] were prepared from the appropriate carboxamide and alcohol,following similar procedures to that described in example 54. Ex R1 R3Data 55

n-Bu δ(CDCl₃): 1.02(6H, m), 1.40(3H, t), 1.57(2H, m), 1.94(4H, m),2.16(2H, m), 2.37(3H, s), 2.41(2H, q), 2.56(6H, m), 3.03(4H, m), 3.15(4H, m), 4.22(1H, m), 4.66(2H, t), 8.62(1H, d), 9.01(1H, d), 10.55(1H,s). 56

δ(CDCl₃): 1.02(3H, t), 1.12(6H, d), 1.42(3H, t), 2.31(7H, m), 2.42(2H,q), 2.57(4H, m), 2.90(2H, t), 3.06(2H, q), 3.16(4H, m), 4.38-4.47 (4H,m), 8.61(1H, d), 9.01(1H, d), 10.60 (1H, s). 57

n-Bu δ(CDCl₃): 1.01(6H, t), 1.40(3H, t), 1.56(2H, m), 1.95(2H, m),2.17(2H, m), 2.21(6H, s), 2.24(2H, t), 2.40(2H, q), 2.57(4H, m), 3.06(2H, q), 3.17(4H, m), 4.37(2H, t), 4.65(2H, t), 8.61(1H, d), 9.02(1H,d), 10.59(1H, s). 58

δ(CDCl₃): 1.02(3H, t), 1.40(3H, t), 2.17(2H, m), 2.21(6H, s), 2.27(2H,t), 2.40(2H, q), 2.57 (4H, m), 3.05(2H, q), 3.17(4H, m), 4.37(2H, t),5.77(2H, s), 7.39(3H, m), 7.52(2H, m), 8.63 (1H, d), 9.01(1H, d),10.54(1H, s).

EXAMPLE 595-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-1-[2-(dimethylamino)-2-oxoethyl]-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneand EXAMPLE 605-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-(dimethylamino)-2-oxoethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0551]

[0552] Sodium hydride (13 mg, 60% dispersion in mineral oil, 0.33 mmol)was added to a solution of the title compound from preparation 59 (145mg, 0.30 mmol) in tetrahydrofuran (2 ml) and the solution stirred for 30minutes. 2-Chloro-N,N-dimethylacetamide (40 mg, 0.034 mmol) was addedand the reaction stirred at room temperature for 16 hours, followed by afurther 16 hours at 60° C. The cooled mixture was treated with aqueoussodium bicarbonate solution (15 ml) and extracted with ethyl acetate(2×15 ml). The combined organic extracts were dried (MgSO₄) andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using dichloromethane:methanol(96.5:3.5) as eluant, and repeated using ethyl acetate:diethylamine(90:10) as eluant, to afford the title compound of example 59, 20 mg,

[0553] δ (CDCl₃): 1.03 (6H, t), 1.41 (3H, t), 1.59 (2H, m), 1.95 (2H,m), 2.4.1 (2H, q), 2.57 (4H, m), 3.00 (5H, m), 3.15 (7H, m), 4.66 (2H,t), 5.44 (2H, s), 8.63 (1H, d), 9.10 (1H, d), 10.85 (1H, s).

[0554] and the title compound of example 60, 45 mg.

[0555] δ (CDCl₃): 1.01 (6H, t), 1.42 (3H, t), 1.55 (2H, m), 1.94 (2H,m), 2.40 (2H, q), 2.55 (4H, m), 3.00 (5H, m), 3.14 (7H, m), 4.64 (2H,t), 5.19 (2H, s), 8.61 (1H, d), 9.01 (1H, d), 10.58 (1H, s).

EXAMPLE 615-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-{2-methyl(methylsulphonyl)amino]ethyl}-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0556]

[0557] Trifluoroacetic acid (1 ml) was added to a solution of the titlecompound from preparation 62 (76 mg, 0.117 mmol) in dichloromethane (1ml), and the solution stirred for 2½ hours at room temperature. Themixture was evaporated under reduced pressure, the residue trituratedwell with ether, and the resulting precipitate, filtered and dried togive a white powder.

[0558] Methanesulphonyl chloride (20 μl, 0.26 mmol) was added to asolution of this intermediate in dichloromethane (2 ml) andtriethylamine (65 μl, 0.47 mmol), and the reaction stirred at roomtemperature for 1½ hours. The mixture was treated with saturated aqueoussodium bicarbonate solution (10 ml), and extracted with ethyl acetate(2×10 ml). The combined organic extracts were dried (MgSO₄) andevaporated under reduced pressure to give a gum. The crude product waspurified by column chromatography on silica gel usingdichloromethane:methanol (96:4) as eluant to afford the title compoundas a beige foam, 30 mg.

[0559] δ (CDCl₃): 1.02 (6H, t), 1.42 (3H, t), 1.54 (2H, m), 1.94 (2H,m), 2.41 (2H, q), 2.57 (4H, m), 2.65 (3H, s), 2.80 (3H, s), 3.13 (6H,m), 3.76 (2H, t), 4.52 (2H, t), 4.67 (2H, t), 8.62 (1H, d), 9.04 (1H,d), 10.68 (1H, s).

EXAMPLE 625-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[1-(methylsulphonyl)piperidin-4-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0560]

[0561] The title compound was obtained as a white solid, (34%), from thetitle compound from preparation 67 and methanesulphonyl chloride,following the procedure described in example 61.

[0562] δ (CDCl₃): 1.01 (6H, t), 1.40 (3H, t), 1.55 (2H, m), 1.95 (2H,m), 2.08 (2H, m), 2.42 (2H, q), 2.57 (6H, m), 2.90 (3H, s), 3.01-3.18(8H, m), 4.01 (2H, m), 4.42 (1H, m), 4.66 (2H, t), 8.62 (1H, d), 9.01(1H, d), 10.60 (1H, s).

EXAMPLE 635-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(4-nitrophenyl)-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0563]

[0564] Potassium bis(trimethylsilyl)amide (134 mg, 0.67 mmol) was addedto a suspension of the title compound from preparation 49 (200 mg, 0.33mmol) and ethyl acetate (50 μl, 0.51 mmol) in ethanol (5 ml) and thereaction mixture heated at 120° C. in a sealed vessel for 12 hours. Thecooled reaction was concentrated under reduced pressure and the residuepartitioned between ethyl acetate and water, and the layers separated.The aqueous phase was extracted with ethyl acetate, the combined organicsolutions dried (MgSO₄), and evaporated under reduced pressure. Thecrude product was purified by column chromatography on silica gel usingdichloromethane:methanol (98:2) as eluant to give the title compound asa yellow oil, 10 mg.

[0565] δ (CDCl₃): 1.02 (3H, t), 1.36 (3H, t), 1.60 (3H, t), 2.41 (2H,q), 2.57 (4H, m), 3.17 (6H, m), 4.78 (2H, q), 7.82 (2H, d), 8.42 (2H,d), 8.66 (1H, d), 9.07 (1H, d), 10.78 (1H, br s).

[0566] LRMS: m/z 583 (M+1)⁺

EXAMPLE 642-(4-Aminophenyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0567]

[0568] A solution of the title compound from example 63 (100 mg, 0.17mmol) in methanol (2 ml) was added to a suspension of iron powder (29mg, 0.52 mmol) in ammonium chloride (45 mg, 0.85 mmol) in water (2 ml),and the reaction heated at 60° C. for 1 hour. The cooled mixture wasfiltered, and the filtrate evaporated under reduced pressure to give thetitle compound as a pale brown solid, 93 mg.

[0569] δ (CDCl₃): 1.02 (3H, t), 1.26 (3H, t), 1.59 (3H, t), 2.41 (2H,q), 2.57 (4H, m), 3.03 (2H, q), 3.16 (4H, m), 3.94 (2H, s), 4.77 (2H,q), 6.78 (2H, d), 7.27 (2H, d), 8.63 (1H, d), 9.07 (1H, d), 10.66 (1H,s).

[0570] LRMS: m/z 553 (M+1)⁺

EXAMPLE 655-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-{4-[(methylsulphonyl)amino]phenyl}-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0571]

[0572] Methanesulphonyl chloride (15 μl, 0.19 mmol) was added to anice-cooled solution of the title compound from example 64 (93 mg, 0.17mmol) in pyridine (2 ml), and the reaction allowed to warm to roomtemperature, and stirred for 90 minutes. Tlc analysis showed startingmaterial remaining, so additional methanesulphonyl chloride (15 μl, 0.19mmol) was added, and the reaction stirred for a further hour. Thereaction was quenched by the addition of aqueous ammonium chloridesolution, and extracted with ethyl acetate. The combined organicextracts were dried (MgSO₄) and concentrated under reduced pressure. Theresidual solid was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (90:10:1) as eluant, then repeatedusing dichloromethane:methanol:0.88 ammonia (95:5:1) to afford the titlecompound, 36 mg.

[0573] δ (CDCl₃): 1.03 (3H, t), 1.34 (3H, t), 1.59 (3H, t), 2.42 (2H,q), 2.58 (4H, m), 3.14 (9H, m), 4.78 (2H, q), 6.92 (1H, s), 7.44 (2H,d), 7.58 (2H, d), 8.65 (1H, d), 9.07 (1H, d), 10.75 (1H, s).

[0574] LRMS: m/z 631 (M+1)⁺

EXAMPLE 665-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0575]

[0576] Pyridine (0.1 ml, 1.08 mmol) was added to a mixture of the titlecompound from preparation 58 (250 mg, 0.64 mmol), copper (II) acetatemonohydrate (145 mg, 0.72 mmol), benzeneboronic acid (132 mg, 1.08 mmol)and 4 Å molecular sieves (392 mg) in dichloromethane (5 ml), and thereaction stirred at room temperature for 4 days. The reaction mixturewas filtered and the filtrate evaporated under reduced pressure. Thecrude product was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (97:3:0.5) as eluant, andtriturated with ether:hexane. The resulting solid was filtered andrecrystallised from isopropanol:dichloromethane to give the titlecompound as a solid, 200 mg.

[0577] δ (CDCl₃): 1.02 (3H, t), 1.47 (3H, t), 1.60 (3H, t), 2.42 (2H,q), 2.58 (4H, m), 3.10 (2H, q), 3.17 (4H, m), 4.76 (2H, q), 7.40 (1H,m), 7.51 (2H, m), 7.80 (2H, d), 8.67 (1H, d), 9.16 (1H, s), 10.90 (1H,s).

[0578] LRMS: m/z 538 (M+1)⁺

EXAMPLE 672-(4-Cyanophenyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0579]

[0580] A mixture of the title compound from preparation 58 (100 mg, 0.22mmol), copper (II) acetate monohydrate (58 mg, 0.29 mmol),4-cyanobenzeneboronic acid (63 mg, 0.44 mmol) and 4 Å molecular sieves(156 mg) in pyridine (1 ml) and N-methylpyrrolidine (1 ml) wasirradiated by microwave at full power for 3×10 seconds, followed by 2×20seconds. The mixture was evaporated under reduced pressure and theresidue purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant. The productwas recrystallised from dichloromethane:isopropanol to give the titlecompound, 45 mg.

[0581] δ (CDCl₃): 1.03 (3H, t), 1.49 (3H, t), 1.62 (3H, t), 2.42 (2H,q), 2.58 (4H, m), 3.08 (2H, q), 3.17 (4H, m), 4.58 (2H, q), 7.79 (2H,d), 8.14 (2H, d), 8.70 (1H, d), 9.16 (1H, d), 11.09 (1H, s).

[0582] LRMS: m/z 563 (M+1)⁺

EXAMPLE 685-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(pyridin-2-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneditrifluoroacetate

[0583]

[0584] Tris(dibenzylideneacetone)dipalladium (0) (8 mg, 0.009 mmol),R-BINAP (8 mg, 0.013 mmol), sodium tert-butoxide (41 mg, 0.43 mmol) and2-bromopyridine (50 μl, 0.52 mmol) were added to a solution of the titlecompound from preparation 58 (200 mg, 0.43 mmol) in toluene (3 ml), andthe reaction heated at 70° C. for 16 hours. The cooled mixture wasevaporated under reduced pressure and the residue filtered throughsilica gel, using dichloromethane:methanol (80:20) as eluant. Theproduct was purified by reverse phase HPLC on silica gel, using anelution gradient of acetonitrile:0.1% aqueous trifluoroacetic acid (5:95to 85:15) to afford the title compound, as a solid, 13 mg.

[0585] δ (CDCl₃): 1.36 (3H, t), 1.48 (3H, t), 1.57 (3H, t), 3.00 (2H,m), 3.14 (6H, m), 3.70 (2H, m), 3.96 (2H, m), 4.77 (2H, q), 7.52 (1H,m), 8.15-8.26 (2H, m), 8.69 (2H, m), 8.92 (1H, d), 10.80-11.00 (1H, s).

[0586] LRMS: m/z 539 (M+1)⁺

EXAMPLE 695-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(pyrazin-2-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-onedi-trifluoroacetate

[0587]

[0588] Cesium carbonate (353 mg, 1.09 mmol) followed by 2-chloropyrazine(100 μl, 1.12 mmol) were added to a solution of the title compound frompreparation 58 (500 mg, 1.08 mmol) in N,N-dimethylformamide (10 ml), andthe reaction heated at 120° C. for 18 hours. The cooled mixture wasevaporated under reduced pressure and the residue was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(98:2:1) as eluant. The product was further purified by reverse phaseHPLC on silica gel, using an elution gradient of acetonitrile:0.1%aqueous trifluoroacetic acid (5:95 to 50:50) to afford the titlecompound, 86 mg.

[0589] δ (CDCl₃): 1.38 (6H, 2xt), 1.58 (3H, t), 2.98-3.22 (6H, m), 3.54(2H, q), 3.76 (2H, m), 4.00 (2H, m), 4.78 (2H, q), 8.57-8.74 (3H, m),8.98 (1H, d), 9.57 (1H, s).

[0590] LRMS: m/z 540 (M+1)⁺

EXAMPLE 705-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(thiazol-2-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-onetrifluoroacetate

[0591]

[0592] The title compound was obtained, (7%) from the title compoundfrom preparation 58 and 2-bromothiazole, following a similar procedureto that described in example 69.

[0593] δ (CD₃OD): 1.28-1.41 (6H, m), 1.48 (3H, t), 3.20-3.34 (6H, m),3.34-3.60 (6H, m), 4.65 (2H, q), 7.59 (1H, d), 7.78 (1H, d), 8.58 (1H,d), 8.78 (1H, d).

[0594] LRMS: m/z 545 (M+1)⁺

EXAMPLE 712-(6-Chloropyrimidin-4-yl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0595]

[0596] Sodium hydride (22 mg, 60% dispersion in mineral oil, 0.55 mmol)was added to an ice-cooled solution of the title compound frompreparation 58 (250 mg, 0.54 mmol) in tetrahydrofuran (5 ml), and thesolution then allowed to warm to room temperature.4,6-Dichloropyrimidine (80 mg, 0.54 mmol) was added, and the reactionstirred at 65° C. for 18 hours. The cooled mixture was evaporated underreduced pressure and the residue purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) aseluant. The product was triturated with dichloromethane to afford thetitle compound as a pale yellow solid, 5 mg.

[0597] δ (CDCl₃): 1.02 (3H, t), 1.40 (3H, t), 1.60 (3H, t), 2.42 (2H,q), 2.58 (4H, m), 3.16 (4H, m), 3.62 (2H, q), 4.78 (2H, q), 8.40 (1H,s), 8.67 (1H, d), 8.97 (1H, s), 9.10 (1H, d), 10.79 (1H, s).

[0598] LRMS: m/z 574, 576 (M+1)⁺

EXAMPLE 725-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(pyrimidin-2-yl)-2,6-dihydro-7H-pyrazolo[4,3-dl]pyrimidin-7-one

[0599]

[0600] The title compound was obtained (8%), from the compound frompreparation 58 and 2-chloropyrimidine, following a similar procedure tothat described in example 71.

[0601] Found: C, 53.33; H, 5.36; N, 23.12. C₂₄H₂₉N₉O₄S requires C,53.42; H, 5.42; N, 23.36%.

[0602] δ (CDCl₃): 1.03 (3H, t), 1.37 (3H, t), 1.59 (3H, t), 2.41 (2H,q), 2.58 (4H, m), 3.17 (4H, m), 3.55 (2H, q), 4.78 (2H, q), 7.42 (1H,m), 8.64 (1H, d), 8.95 (2H, d), 9.11 (1H, d), 10.73 (1H, s).

[0603] LRMS: m/z 540 (M+1)⁺

EXAMPLE 735-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-3-ethyl-2-(pyrimidin-2-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0604]

[0605] Sodium hydride (19 mg, 60% dispersion in mineral oil, 0.48 mmol)was added to an ice-cold solution of the title compound from preparation69 (200 mg, 0.41 mmol) in tetrahydrofuran (4 ml), and the solutionstirred for 30 minutes. 2-Chloropyrimidine (56 mg, 0.48 mmol) was added,and the reaction heated under reflux for 18 hours. The mixture wasevaporated under reduced pressure, the residue diluted with water, andextracted with dichloromethane. The combined organic extracts were dried(MgSO₄), and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (100:0 to 95:5) to give the titlecompound, 31 mg.

[0606] δ (CDCl₃): 1.02 (3H, t), 1.36 (3H, t), 2.42 (2H, q), 2.58 (4H,m), 3.18 (4H, m), 3.50 (2H, q), 3.58 (3H, s), 3.88 (2H, t), 4.80 (2H,t), 7.42 (1H, m), 8.64 (1H, d), 8.95 (2H, d), 9.02 (1H, d), 10.82 (1H,s).

[0607] LRMS: m/z 570 (M+1)⁺

EXAMPLE 742-(1,3-Benzoxazol-2-yl)-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0608]

[0609] The title compound was obtained (35%), from the title compoundfrom preparation 69 and 2-chlorobenzoxazole, following the proceduredescribed in example 73.

[0610] δ (CDCl₃): 1.02 (3H, t), 1.50 (3H, t), 2.42 (2H, q), 2.58 (4H,m), 3.18 (4H, m), 3.59 (3H, s), 3.62 (2H, q), 3.87 (2H, t), 4.80 (2H,t), 7.43 (2H, m), 7.64 (1H, m), 7.80 (1H, m), 8.65 (1H, d), 9.02 (1H,d), 10.98 (1H, s).

[0611] LRMS: m/z 609 (M+1)⁺

EXAMPLE 753-Ethyl-5-[5-(4-ethylpierazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0612]

[0613] Potassium bis(trimethylsilyl)amide (294 mg, 1.47 mmol) was addedto a solution of the compound from example 66 (200 mg, 0.37 mmol) in2-methoxyethanol (10 ml), and the reaction heated under reflux for 18hours. The mixture was evaporated under reduced pressure and the residuepurified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (97:3:0.5) as eluant. The productwas recrystallised from dichloromethane:iso-propanol to give the desiredcompound as a white solid, 82 mg.

[0614] Found: C, 57.06; H, 5.83; N, 17.27. C₂₇H₃₅N₇O₅S requires C,57.13; H, 5.86; N, 17.27%.

[0615] δ (CDCl₃): 1.02 (3H, t), 1.46 (3H, t), 2.42 (2H, q), 2.57 (4H,m), 3.16 (2H, q), 3.17 (4H, m), 3.56 (3H, s), 3.84 (2H, t), 4.58 (2H,t), 7.38 (1H, m), 7.48 (2H, m), 7.80 (2H, m), 8.64 (1H, m), 9.04 (1H,m), 11.10 (1H, brs).

[0616] LRMS: m/z 568 (M+1)⁺

EXAMPLE 765-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-1-(2-methoxyethyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0617]

[0618] A mixture of the title compound of preparation 57 (440 mg, 0.82mmol), and potassium bis(trimethylsilyl)amide (196 mg, 0.98 mmol) inethanol (15 ml) was heated at 100° C. for 18 hours, in a sealed vessel.The cooled mixture was concentrated under reduced pressure, the residuepartitioned between ethyl acetate (20 ml) and brine (10 ml), and thelayers separated. The organic phase was separated, dried (MgSO₄), andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel, using an elution gradient ofdichloromethane:methanol (100:0 to 95:5) to afford the title compound,275 mg, as a pale yellow solid.

[0619] δ (CDCl₃) 1.02 (3H, t), 1.60 (3H, t), 1.86 (2H, m), 2.29 (3H, s),2.52 (4H, m), 2.95 (2H, t), 3.16 (4H, m), 3.35 (3H, s), 3.87 (2H, t),4.78 (4H, m), 8.64 (1H, s), 9.09 (1H, s), 10.81 (1H, s).

[0620] LRMS: m/z 520 (M+1)⁺

EXAMPLE 775-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-1.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0621]

[0622] A mixture of the title compound of preparation 56 (1.02 g, 1.9mmol) and potassium tert-butoxide (533 mg, 4.75 mmol) in ethanol (40 ml)was heated at 100° C. in a sealed vessel for 18 hours. The cooledmixture was concentrated under reduced pressure and the residuepartitioned between ethyl acetate (50 ml) and brine (25 ml), and thelayers separated. The organic phase was washed with brine (25 ml), dried(MgSO₄), and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel, using an elutiongradient of ethyl acetate:methanol (100:0 to 90:10) to afford the titlecompound, 698 mg, as a pale yellow solid.

[0623] Found: C, 53.00; H, 6.39; N, 18.87 C₂₃H₃₃N₇O₅S requires C, 53.16;H, 6.40; N, 18.87%

[0624] δ (CDCl₃): 1.03 (3H, t), 1.40 (3H, t), 1.59 (3H, t), 2.41 (2H,q), 2.57 (4H, m), 3.00 (2H, q), 3.15 (4H, m), 3.35 (3H, s), 3.88 (2H,t), 4.78 (4H, m), 8.63 (1H, s), 9.09 (1H, s), 10.83 (1H, s).

[0625] LRMS: m/z 520 (M+1)⁺

EXAMPLE 782-Cyclobutylmethyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(pyrrolidin-1-yl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0626]

[0627] A mixture of the title compound from example 7 (200 mg, 0.38mmol) and copper sulphate pentahydrate (74 mg, 0.30 mmol) in pyrrolidine(4 ml) was heated under reflux for 18 hours. The cooled mixture wasconcentrated under reduced pressure and the residue purified by columnchromatography on silica gel twice using an elution gradient ofdichloromethane:methanol (100:0 to 95:5) to give the title compound as apale brown solid, 109 mg.

[0628] δ (CDCl₃): 1.04 (3H, m), 1.38 (3H, t), 1.90 (8H, m), 2.10 (2H,m), 2.37-2.68 (5H, m), 3.00 (2H, q), 3.14 (4H, m), 3.42 (4H, m), 4.32(2H, d), 8.00 (1H, s), 8.58 (1H, s).

[0629] LRMS: m/z 555 (M+1)⁺

EXAMPLE 792-Cyclobutyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0630]

[0631] A mixture of the compound from preparation 83 (440 mg, 0.83mmol), potassium bis(trimethylsilyl)amide (500 mg, 2.51 mmol) and ethylacetate (100 μl, 1.0 mmol) in ethanol (10 ml) was heated at 120° C. in asealed vessel for 18 hours. The cooled mixture was evaporated underreduced pressure and the residue was purified by column chromatographyon silica gel using an elution gradient of dichloromethane:methanol(100:0 to 95:5) to afford the title compound, 263 mg.

[0632]¹Hnmr (CDCl₃, 300 MHz) δ: 1.01 (3H, t), 1.35 (3H, t), 1.58 (3H,t), 1.96 (2H, m), 2.38-2.60 (8H, m), 2.98 (4H, m), 3.14 (4H, m), 4.76(2H, q), 4.96 (1H, m), 8.61 (1H, d), 9.02 (1H, d), 10.59 (1H, s).

[0633] LRMS: m/z 516 (MH⁺)

EXAMPLE 802-Cyclopentyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0634]

[0635] Potasssium bis(trimethylsilyl)amide (450 mg, 2.25 mmol) was addedto a suspension of the compound from preparation 84 (243 mg, 0.45 mmol)in ethanol (5 ml), and the mixture heated at 100° C. in a Reactivial®for 24 hours. Tlc analysis showed starting material remaining, soadditional potassium bis(trimethylsilyl)amide (250 mg, 1.25 mmol) andethyl acetate (3 drops) were added, and the reaction heated at 111° C.for 18 hours. The cooled mixture was partitioned between ethyl acetateand sodium bicarbonate solution, and the phases separated. The aqueouslayer was extracted with ethyl acetate (2×), the combined organicsolutions washed with brine, dried (MgSO₄), and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using methanol:dichloromethane (2:98) as eluant, andtriturated with ether to afford the title compound as a white powder, 55mg.

[0636]¹Hnmr (CDCl₃, 400 MHz) δ: 1.02 (3H, t), 1.39 (3H, t), 1.55 (3H,t), 1.72 (2H, m), 2.05 (2H, m), 2.17 (2H, m), 2.30 (2H, m), 2.40 (2H,q), 2.56 (4H, m), 3.04 (2H, q), 3.16 (4H, m), 4.76 (2H, q), 4.82 (1H,m), 8.61 (1H, s), 9.02 (1H, s), 10.55 (1H, s).

[0637] LRMS: m/z 530.8 (MH⁺)

[0638] Anal. Found: C, 57.17; H, 6.65; N, 18.14. C₂₅H₃₅N₇O₄S requires C,56.69; H, 6.66; N, 18.51%.

EXAMPLE 812-Cyclopentylmethyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0639]

[0640] The title compound was obtained as a white powder in 41% yieldfrom the compound from preparation 85, following the procedure describedin example 80.

[0641]¹Hnmr (CDCl₃, 0.400 MHz) δ: 1.01 (3H, t), 1.30 (4H, m), 1.40 (3H,t), 1.54 (5H, m), 1.70 (2H, m), 2.40 (2H, q), 2.56 (4H, m), 2.63 (1H,m), 3.02 (2H, q), 3.12 (4H, m), 4.20 (2H, d), 4.74 (2H, q), 8.61 (1H,d), 9.03 (1H, d), 10.60 (1H, s).

[0642] LRMS: m/z 547.7 (MH⁺)

EXAMPLE 822-Cyclohexyl-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2.6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0643]

[0644] The title compound was obtained as a white solid in 35% yield,from the compound of preparation 86, following a similar procedure tothat described in example 80.

[0645]¹Hnmr (CDCl₃, 400 MHz) δ: 1.02 (3H, t), 1.30-1.50 (6H, m), 1.58(3H, t), 1.78 (1H, m), 1.98 (4H, m), 2.22 (2H, m), 2.41 (2H, q), 2.55(4H, m), 3.05 (2H, q), 3.16 (4H, m), 4.23 (1H, m), 4.75 (2H, q), 8.61(1H, s), 9.01 (1H, s), 10.54 (1H, s).

[0646] LRMS: m/z 548.8 (MH⁺)

[0647] Anal. Found: C, 57.23; H, 6.96; N, 17.54. C₂₆H₃₇N₇O₄S requires C,57.44; H, 6.86; N, 18.03%.

EXAMPLE 835-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(2-ethoxyethyl)-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0648]

[0649] Potassium bis(trimethylsilyl)amide (256 mg, 1.28 mmol) was addedto a solution of the compound from preparation 70 (170 mg, 0.30 mmol)and ethyl acetate (30 mg, 0.33 mmol) in ethanol (5 ml), and the reactionheated at 130° C. for 6 hours. The cooled mixture was evaporated underreduced pressure and the residual yellow solid was purified by columnchromatography on silica gel using dichloromethane:methanol (97:3) aseluant. The product was triturated with isopropyl ether then re-purifiedby column chromatography using an elution gradient ofdichloromethane:methanol (100:0 to 90:10) to afford the title compound,20 mg.

[0650]¹Hnmr (CDCl₃, 400 MHz) δ: 1.00 (3H, t), 1.10 (3H, t), 1.40 (3H,t), 1.54 (3H, t), 2.40 (2H, q), 2.50 (4H, m), 3.05 (2H, q), 3.10 (4H,m), 3.40 (2H, q), 3.90 (2H, t), 4.42 (2H, t), 4.70 (2H, q), 8.60 (1H,s), 9.00 (1H, s), 10.60 (1H, s).

[0651] LRMS: m/z 535 (MH⁺)

[0652] Anal. Found: C, 53.97; H, 6.64; N, 18.14. C₂₄H₃₅N₇O₅S requires C,54.02; H, 6.61; N, 18.37%.

EXAMPLE 845-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[(1S)-1-methyl-2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0653]

[0654] Potassium bis(trimethylsilyl)amide (2.10 g, 10.5 mmol) was addedto a solution of the compound from preparation 90 (1.20 g, 2.17 mmol)and ethyl acetate (200%, 2.02 mmol) in ethanol (40 ml), and the reactionheated in a sealed vessel at 130° C. for 6 hours. The cooled mixture wasconcentrated under reduced pressure and the residue partitioned betweenethyl acetate and water, and neutralised by the addition of solid carbondioxide. The layers were separated, the aqueous phase extracted withethyl acetate, and the combined organic solutions dried (Na₂SO₄) andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane:methanol (99:1 to 96:4), and the product crystallisedfrom ether/pentane to afford the title compound, 250 mg.

[0655]¹Hnmr (CDCl₃, 300 MHz) δ: 1.02 (3H, t), 1.39 (3H, t), 1.58 (6H,m), 2.41 (2H, q), 2.56 (4H, m), 3.08 (6H, m), 3.22 (3H, s), 3.74 (1H,m), 3.98 (1H, m), 4.74 (3H, m), 8.62 (1H, d), 9.02 (1H, d), 10.58 (1H,s).

[0656] Anal. Found: C, 53.79; H, 6.61; N, 18.26. C₂₄H₃₅N₇O₅S requires C,54.02; H, 6.61; N, 18.38%.

EXAMPLE 855-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[(1R)-1-methyl-2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0657]

[0658] The title compound was obtained as a crystalline solid in 17%yield from the compound from preparation 89, following a similarprocedure to that described in example 84.

[0659]¹Hnmr (CDCl₃, 300 MHz) δ: 1.02 (3H, t), 1.39 (3H, t), 1.58 (6H,m), 2.40 (2H, q), 2.55 (4H, m), 3.08 (6H, m), 3.22 (3H, s), 3.70 (1H,m), 3.98 (1H, m), 4.72 (3H, m), 8.61 (1H, d), 9.02 (1H, d), 10.58 (1H,s).

[0660] LRMS: m/z 534.4 (MH⁺)

[0661] Anal. Found: C, 53.67; H, 6.62; N, 18.27. C₂₄H₃₅N₇O₅S requires C,54.02; H, 6.61; N, 18.38%.

EXAMPLE 865-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(3-methoxy-n-propyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0662]

[0663] Potassium bis(trimethylsilyl)amide (145 mg, 0.72 mmol) was addedto a solution of the compound from preparation 88 (200 mg, 0.36 mmol) in3-methyl-3-pentanol (4 ml), and the reaction heated at 130° C. for 10hours, then cooled. The mixture was evaporated under reduced pressureand the residue purified twice by column chromatography on silica gelusing dichloromethane:methanol (97:3) as eluant, to afford the titlecompound, 40 mg.

[0664]¹Hnmr (CDCl₃, 400 MHz) δ: 1.00 (3H, t), 1.40 (3H, t), 1.57 (3H,t), 2.20 (2H, m), 2.42 (2H, m), 2.60 (4H, m), 3.03 (2H, q), 3.15 (4H,m), 3.30 (3H, s), 3.35 (2H, t), 4.40 (2H, t), 4.72 (2H, q), 8.60 (1H,s), 9.00 (1H, s), 10.60 (H, br s).

[0665] LRMS: m/z 535 (MH⁺)

EXAMPLE 872-Cyclobutyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0666]

[0667] A mixture of the compound from preparation 83 (238 mg, 0.45 mmol)and potassium bis(trimethylsilyl)amide (450 mg, 2.25 mmol) in2-methoxyethanol (5 ml) was stirred under reflux for 6 hours. The cooledmixture was partitioned between ethyl acetate and sodium bicarbonatesolution, and the layers separated. The organic phase was washed withbrine, dried (MgSO₄) and evaporated under reduced pressure. The residualorange oil was purified by column chromatography on silica gel usingdichloromethane:methanol (98:2) as eluant to afford the title compoundas an off-white foam, 150 mg.

[0668]¹Hnmr (CDCl₃, 300 MHz) δ: 1.00 (3H, t), 1.38 (3H, t), 1.85-2.05(2H, m), 2.40 (2H, q), 2.45 (2H, m), 2.54 (4H, m), 2.90-3.05 (4H, m),3.15 (4H, m), 3.55 (3H, s), 3.80 (2H, m), 4.74 (2H, m), 4.95 (1H, m),8.60 (1H, s), 8.98 (1H, s), 10.75 (1H, s).

[0669] LRMS: m/z 546.4 (MH⁺)

[0670] Anal. Found: C, 54.53; H, 6.59; N, 17.77. C₂₅H₃₅N₇O₅S requires C,55.03; H, 6.47; N, 17.97%.

EXAMPLES 88 TO 92

[0671] The compounds of the following general structure:

[0672] were prepared from the corresponding pyrazole carboxamide and2-methoxyethanol, following a similar method to that described inexample 87. Ex Yield no. R (%) Data 88¹

15 ¹Hnmr(CDCl₃, 400MHz)δ: 0.43(2H, m), 0.60 (2H, m), 0.80(1H, m),1.00(3H, t), 1.40(3H, t), 2.40(2H, q), 2.54(4H, m), 3.00(1H, q),3.07(4H, m), 3.50(3H, s), 3.80(2H, m), 4.20 (2H, d), 4.78(2H, m),8.60(1H, s), 8.97(1H, s), 10.57(1H, br s). Anal. Found: C, 52.68; H,6.27; N, 17.19. C₂₅H₃₅N₇O₅S.H₂O requires C, #53.27; H, 6.26; N, 17.39%.89²

39 ¹Hnmr(CDCl₃, 400MHz)δ: 1.02(3H, t), 1.38 (3H, t), 1.72(2H, m),2.00-2.19(4H, m), 2.28 (2H, m), 2.40(2H, q), 2.56(4H, m), 3.04(2H, q),3.16(4H, m), 3.57(3H, s), 3.86(2H, t), 4.78(2H, t), 4.82(1H, m),8.61(1H, d), 8.98 (1H, d), 10.73(1H, s). LRMS: m/z 560.4(MH⁺) Anal.Found: C, 55.30; H, 6.79; #N, 17.49. C₂₆H₃₇N₇O₅S requires C, 55.80; H,6.66; N, 17.52%. 90²

40 ¹Hnmr(CDCl₃, 400MHz)δ: 1.02(3H, t), 1.32 (2H, m), 1.40(3H, t),1.58(2H, m), 1.70(4H, m), 2.40(2H, q), 2.56(4H, m), 2.62(1H, m),3.01(2H, q), 3.16(4H, m), 3.57(3H, s), 3.86 (2H, t), 4.21(2H, d),4.79(2H, t), 8.61(1H, s), 8.98(1H, s), 10.74(1H, s). LRMS: m/z574.8(MH⁺) Anal. Found: C, 54.88; H, 6.89; #N, 16.63. C₂₇H₃₉N₇O₅S; H₂Orequires C, 54.80; H, 6.98; N, 16.57%. 91

46 ¹Hnmr(CDCl₃, 400NHz)δ: 1.02(3H, t), 1.38 (6H, m), 1.77(1H, m),1.98(4H, m), 2.22(2H, m), 2.41(2H, q), 2.57(4H, m), 3.02(2H, q),3.14(4H, m), 3.56(3H, s), 3.84(2H, t), 4.22 (1H, m), 4.78(2H, t),8.61(1H, d), 8.98(1H, d), 10.71(1H, s). 92

21 ¹Hnmr(CDCl₃, 300MHz)δ: 1.00(3H, t), 1.40 (3H, t), 1.83(2H, m),2.40(2H, q), 2.55(6H, m), 3.06(2H, q), 3.10(4H, m), 3.55(3H, s),3.60(2H, t), 3.80(2H, t), 4.20(2H, m), 4.48 (1H, m), 4.80(2H, t),8.60(1H, s), 9.00(1H, s), 10.80(1H, s). LRMS: m/z 576.6(MH⁺)

EXAMPLE 935-[2-n-Butoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[0673]

[0674] Potassium bis(trimethylsilyl)amide (123 mg, 0.62 mmol) was addedto a solution of the compound from preparation 27 (162 mg, 0.31 mmol) inn-butanol, and the reaction mixture heated at 120° C. for 18 hours. Thecooled mixture was concentrated under reduced pressure and the residualyellow oil purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol:0.88 ammonia (98:2:0.2 to95:5:0.5). The product was triturated with ether to give the titlecompound as a white solid, 78 mg.

[0675]¹Hnmr (CDCl₃, 300 MHz) δ: 1.03 (3H, t), 1.41 (3H, t), 1.54 (2H,m), 1.94 (2H, m), 2.28 (3H, s), 2.51 (4H, m), 3.07 (2H, m), 3.14 (4H,m), 3.30 (3H, s), 3.95 (2H, t), 4.46 (2H, t), 4.67 (2H, t), 8.63 (1H,m), 9.04 (1H, m), 10.60 (1H, m).

[0676] Anal. Found: C, 53.64; H, 6.64; N, 18.15. C₂₄H₃₅N₇O₅S requires C,54.02; H, 6.61; N, 18.37%.

EXAMPLE 943-Ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[(1S)-1-methylpropyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[0677]

[0678] Potassium bis(trimethylsilyl)amide (960 mg, 4.8 mmol) was addedto a solution of the compound from preparation 93 (500 mg, 0.96 mmol) in2-methoxyethanol (15 ml), and the reaction heated at 130° C. for 5hours. The cooled reaction mixture was partitioned between ethyl acetateand water, and the mixture neutralised using solid carbon dioxide. Thelayers were separated, the organic phase washed with water, dried(MgSO₄) and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (99:1 to 96:4) to give an oil. Thiswas triturated with ether, to afford the title compound as a whitepowder, 170 mg.

[0679]¹Hnmr (CDCl₃, 400 MHz) δ: 0.80 (3H, t), 1.40 (3H, t), 1.60 (3H,d), 1.90 (1H, m), 2.20 (1H, m), 2.22 (3H, s), 2.50 (4H, m), 3.00 (2H,m), 3.10 (4H, m), 3.58 (3H, s), 3.80 (2H, m), 4.40 (1H, m), 4.80 (2H,m), 8.60 (1H, s), 9.00 (1H, s), 10.70 (1H, s).

[0680] LRMS: m/z 534.6 (MH⁺)

[0681] Anal. Found: C, 54.20; H, 6.68; N, 18.39. C₂₄H₃₅N₇O₅S requires C,54.08; H, 6.71; N, 18.40%.

[0682] [α]_(D)+26.0° (c=0.1, methanol).

EXAMPLE 953-Ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[(1R)-1-methylpropyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[0683]

[0684] The title compound was obtained as a white powder in 23% yieldfrom the compound from preparation 94 and 2-methoxyethanol, followingthe procedure described in example 94.

[0685]¹Hnmr (CDCl₃, 400 MHz) δ: 0.80 (3H, t), 1.40 (3H, t), 1.60 (3H,d), 1.90 (1H, m), 2.20 (1H, m), 2.22 (3H, s), 2.50 (4H, m), 3.00 (2H,m), 3.10 (4H, m), 3.58 (3H, s), 3.80 (2H, m), 4.40 (1H, m), 4.80 (2H,m), 8.60 (1H, s), 9.00 (1H, s), 10.70 (1H, s).

[0686] LRMS: m/z 534.6 (MH⁺)

EXAMPLE 962-n-Butyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[0687]

[0688] The title compound was obtained as a solid in 54% yield from thecompound from preparation 91 and 2-methoxyethanol, following a similarprocedure to that described in example 95.

[0689]¹Hnmr (CDCl₃, 400 MHz) δ: 0.95 (3H, t), 1.40 (5H, m), 1.97 (2H,m), 2.35 (3H, s), 2.58 (4H, m), 3.01 (2H, q), 3.18 (4H, m), 3.56 (3H,s), 3.85 (2H, t), 4.28 (2H, t), 4.78 (2H, t), 8.62 (1H, d), 8.98 (1H,d), 10.75 (1H, s).

[0690] LRMS: m/z 535 (MH⁺)

EXAMPLE 972-Cyclopropylmethyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[0691]

[0692] The title compound was obtained as a solid in 41% yield from thecompound from preparation 92 and 2-methoxyethanol, following a similarprocedure to that described in example 95.

[0693]¹Hnmr (CDCl₃, 400 MHz) δ: 0.46 (2H, m), 0.62 (2H, m), 1.40 (4H,m), 2.27 (3H, s), 2.50 (4H, m), 3.05 (2H, q), 3.16 (4H, m), 3.57 (3H,s), 3.84 (2H, t), 4.20 (2H, d), 4.58 (2H, t), 8.61 (1H, d), 8.98 (1H,d), 10.77 (1H, s).

[0694] LRMS: m/z 532.2 (MH⁺)

EXAMPLE 982-Cyclobutylmethyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(tetrahydro-2-furanylmethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[0695]

[0696] A mixture of the compound from example 7 (200 mg, 0.38 mmol) andpotassium bis(trimethylsilyl)amide (371 mg, 1.86 mmol) intetrahydrofurfuryl alcohol (2.5 ml) was heated under reflux for 18hours. The cooled mixture was concentrated under reduced pressure, andthe residue purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol (100:0 to 90:10). Theproduct was recrystallised from ether to afford the title compound, 20mg.

[0697]¹Hnmr (CDCl₃, 300 MHz) δ: 1.01 (3H, t), 1.40 (3H, t), 1.75-2.18(10H, m), 2.40 (2H, q), 2.55 (4H, m), 3.00 (3H, m), 3.15 (4H, m), 3.88(1H, m), 4.16 (1H, m), 4.30 (2H, d), 4.38 (1H, m), 4.59 (1H, m), 4.75(1H, m), 8.60 (1H, d), 8.98 (1H, d), 10.73 (1H, s).

[0698] LRMS: m/z 587 (MH⁺)

EXAMPLE 993-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(2-methoxyethoxy)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[0699]

[0700] The title compound was obtained as a solid, from the compoundfrom example 8 and 2-methoxyethanol, following a similar procedure tothat described in example 98.

[0701]¹Hnmr (CDCl₃, 300 MHz) δ: 1.02 (6H, m), 1.84 (2H, m), 2.42 (2H,q), 2.56 (4H, m), 3.01 (2H, t), 3.15 (4H, m), 3.29 (3H, s), 3.57 (3H,s), 3.88 (2H, m), 4.44 (2H, t), 4.78 (2H, t), 8.61 (1H, s), 8.98 (1H,s), 10.76 (1H, s).

[0702] LRMS: m/z 564 (MH⁺)

EXAMPLE 1005-[2-Ethoxy-5-(4-iso-propylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[0703]

[0704] Sodium nitrite (116 mg, 1.68 mmol) was added to a cooled (−20°C.) solution of the amine from preparation 82 (400 mg, 1.12 mmol) inacetic acid (5 ml) and concentrated hydrochloric acid (5 ml), and thesolution allowed to warm to room temperature over 4 hours. The solutionwas then re-cooled to −15° C., liquid sulphur dioxide (3 ml) addedfollowed by a solution of copper (II) chloride (450 mg, 3.34 mmol) inwater (2 ml), and the solution stirred for 2 hours, then allowed to warmto room temperature. The reaction was diluted with water and extractedwith dichloromethane (100 ml). The combined organic extracts were dried(Na₂SO₄), concentrated under reduced pressure and the residue azeotropedwith toluene. The product was dissolved in ethanol (5 ml),N-isopropylpiperazine (500%1, 3.56 mmol) added and the reaction stirredat room temperature for 18 hours. The reaction mixture was evaporatedunder reduced pressure and the crude product purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(96:4:0.5) as eluant. The resulting pale yellow solid was recrystallisedfrom isopropyl ether:dichloromethane to give the title compound, 211 mg.

[0705]¹Hnmr (CDCl₃, 300 MHz) δ: 1.00 (6H, 2xs), 1.40 (3H, t), 1.56 (3H,t), 2.60 (4H, m), 2.66 (1H, m), 3.08 (6H, m), 3.27 (3H, s), 3.92 (2H,t), 4.45 (2H, t), 4.75 (2H, q), 8.61 (1H, d), 9.02 (1H, d), 10.61 (1H,s).

[0706] LRMS: m/z 534.5 (MH⁺)

[0707] Anal. Found: C, 54.00; H, 6.69; N, 18.24. C₂₄H₃₅N₇O₅S requires C,54.02; H, 6.61; N, 18.37%.

EXAMPLE 1015-[2-Ethoxy-5-(4-n-propylpiperazin-1-ylsulphonyl)pyridin-3-yl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[0708]

[0709] The title compound was obtained in 21% yield from the amine ofpreparation 82 and n-propyl piperazine (prepared from the hydrobromidesalt, in the presence of excess triethylamine), following the proceduredescribed in Example 100.

[0710]¹Hnmr (CDCl₃, 300 MHz) δ: 0.84 (3H, t), 1.40 (3H, t), 1.55 (5H,m), 2.30 (2H, m), 2.55 (4H, m), 3.08 (6H, m), 3.28 (3H, s), 3.94 (2H,t), 4.44 (2H, t), 4.75 (2H, q), 8.62 (1H, d), 9.03 (1H, d), 10.61 (1H,s).

[0711] LRMS: m/z 534.4 (MH⁺)

EXAMPLE 1021-(6-Ethoxy-5-[3-ethyl]-6.7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl-3-pyridylsulfonyl)-4-ethylpiperazine•ethylAcetate Solvate

[0712]

[0713] To prepare the compound of Example 8 a mixture ofN-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl) nicotinamide (1.18 kg, 2.2 Mol), potassium tert-butoxide (500g, 4.4 moles) and ethyl acetate (193 g) in ethanol (11.8 L) was heatedat 120° C. for 20 hours. The reaction mixture was then concentratedunder reduced pressure, in total approx. 10 L of solvent were distilled.To the residue water (2.9 L) was added and the mixture stirred at roomtemperature while aqueous HCl was added until pH 7.5 was obtained. Ethylacetate (7.5 L) was added and the two phase mixture was warmed to 55° C.The organic phase was separated and the aqueous phase was extracted withfurther ethyl acetate (3.0 L). The combined organic phases weredistilled at atmospheric pressure to a final volume of 4 L. Theprecipitated solids were granulated at 5° C. for 1 h, filtered andwashed with ethyl acetate (1.2 L) and dried under vacuum. This afforded1-(6-Ethoxy-5-[3-ethyl]-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazineas a light yellow crystalline solid, 877 g, 78%. m.p.=157° C. Found: C,52.65; H, 6.46; N, 17.76. C₂₃H₃₃N₇O₅S. 0.2 C₂H₅CO₂CH₃ requires C, 53.21;H, 6.49; N, 18.25%.

[0714] δ (CDCl₃): 1.07 (3H, t), 1.42 (3H, t), 1.61 (3H, t), 2.44 (2H,q), 2.57 (4H, m), 3.08 (2H, q), 3.15 (4H, m), 3.32 (3H, s), 3.92 (2H,q), 4.48 (2H, q), 4.77 (2H, q), 8.65 (1H, d), 9.06 (1H, d). The spectrumalso has signals that correspond to a solvate with ethyl acetate.

[0715] LRMS: m/z=520 (M+1)⁺

EXAMPLE 1031-{6-ethoxy-5-[3-ethyl-6.7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine

[0716]

[0717] 10 g (0.019 mol) of the compound of Example 8 and Example 102,1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazineethyl acetate solvate, was charged followed by 12 ml/g (120 mls) of 16%water in ethyl alcohol. The slurry was heated to reflux to yield asolution and 6 ml/g (60 mls) distilled off at atmospheric pressure. Thesolution was then cooled to room temperature with crystallisationoccurring at 40° C. The slurry was then cooled to 5-10° C. andgranulated for 30 minutes following which it was filtered and washedwith 2 ml/g ethyl alcohol (20 mls). The damp solid was dried in vacuoovernight at 55-60° C. to yield a white crystalline solid. (Yield 7.6 g,76%). Melting Point 162-165° C.

[0718] δ (CDCl₃): 1.05 (3H,t), 1.42 (3H,t), 1.58 (3H,t), 2.43 (2H,q),2.57 (4H,t), 3.09 (2H, t), 3.15 (4H,t), 3.30 (3H,s), 3.93 (2H,t), 4.48(2H,t), 4.90 (2H,q), 8.65 (1H,d), 9.05 (1H,d), 10.65 (1H,s).

[0719] In the process of Example 103, water and pharmaceuticallyacceptable alcohols such as methanol, ethanol, propanol, butanol andmixtures thereof can be used to prepare the compound of Examples 8 and102.

EXAMPLE 1041-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazineBenzene-Sulfonate Salt

[0720]

[0721] 170 g (0.33 mol) of the compound of Example 103,1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine,was charged followed by a water/2-butanone (4% v/v) at 10 ml/g (1.7litres) and warmed to reflux. 53 g (0.33 mol) of benzene sulfonic aciddissolved in water (23 mls, resulting in 70% w/w solution) was added tothe refluxing solution over 30 minutes.5.3 ml/g (0.9 litres) of2-butanone were striped and replaced and the slurry cooled. The slurrywas cooled to 5-10° C. and granulated for 2 hours after which it wasfiltered and washed with 2 ml/g (0.3 litres) of 2-butanone. The salt wasdried overnight in vacuo at 55-60° C. to yield a white crystallinesolid. Yield 215 g, 96.4%. Mpt 242-244° C.

[0722] δ (DMSO): 1.17 (3H, t), 1.28 (3H, t), 1.35 (3H, t), 2.73 (2H, q),2.97 (2H, q), 3.2 (3H, s), 3.58 (2H, t), 3.78 (3H, t), 3.81 (2H, t),4.49 (2H, t) 4.51 (2H, q), 7.29-7.33 (3H, m), 7.57-7.60 (2H, m), 8.28(1H, d), 8.73 (1H, d), 9.13 (1H,s), 11.90(1H,s).

[0723] The powder X-ray diffraction (PXRD) pattern for this salt, havingMpt 242-244° C., was determined using a Siemens D5000 powder X-raydiffractometer fitted with a theta-theta goniometer, automatic beamdivergence slits, a secondary monochromator and a scintillation counter.The specimen was rotated whilst being irradiated with copper K-alpha1X-rays (Wavelength=1.5046 Angstroms) filtered with a graphitemonochromator (λ=0.15405 nm) with the X-ray tube operated at 40 kWmA.

[0724] The main peaks (in degrees θ) of the PXRD pattern are illustratedin Table I. TABLE I Intensity Intensity Angle % Angle % Angle Intensity% 2-Theta ° % 2-Theta ° % 2-Theta ° % 4.208 8.6 22.294 91.9 34.952 5.57.292 52.5 22.708 13.4 35.497 5.6 8.153 12.6 23.414 12.6 35.830 5.48.422 4.1 23.682 4.7 36.507 4.5 9.426 10.2 24.132 4.6 36.816 8.4 10.957100.0 24.361 13.3 37.047 16.0 12.645 11.4 24.554 12.9 37.641 5.5 14.15018.6 24.844 6.9 38.362 8.7 14.639 3.1 24.902 7.6 38.582 17.7 14.928 2.725.444 15.2 39.203 8.8 15.080 4.9 25.854 43.0 40.549 7.8 15.363 1.826.054 16.4 41.277 6.7 16.070 4.5 26.369 12.5 41.487 11.9 16.245 5.427.016 9.5 42.376 8.4 16.351 11.4 27.706 4.8 42.759 7.1 16.892 33.928.302 7.2 43.450 8.0 17.554 35.1 28.504 10.9 44.400 4.5 18.178 11.828.998 4.0 45.043 8.3 18.562 3.2 29.615 16.1 45.888 6.2 18.903 3.030.197 5.2 46.393 6.2 19.174 3.1 31.039 12.5 46.897 7.3 19.591 31.631.445 7.7 48.197 7.8 20.392 43.3 32.094 6.5 48.373 7.9 20.598 6.832.611 6.4 49.163 5.3 20.965 12.8 32.734 9.3 50.501 6.0 21.136 7.833.014 6.5 50.619 5.9 21.485 32.9 33.110 7.2 52.248 14.6 22.000 24.033.740 3.5 52.746 5.7 34.255 3.4 54.668 5.1

[0725] The same besylate salt, as defined by the XRD pattern describedin Table 1, when made via alternative routes can have a melting point inthe range of from 235-246° C. (measured using a Perkin Elmer DSC7 at aheating rate of 20° C./minute).

EXAMPLE 1041-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazinep-Toluene Sulfonate Salt

[0726]

[0727] 5 g (0.0096 mol) of the compound of Example 103,1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine,was charged followed by 10 ml/g (50 mls) of ethyl alcohol and warmed toreflux. 1.86 g (0.0097 mol) of p-toluene sulfonic acid dissolved in 10mls ethyl alcohol was added to the refluxing solution over 15 seconds.The solution was allowed cool and allowed granulate for 1 hour at <R.T.The slurry was filtered and washed with 3 mlg (15 mls) of ethyl alcohol.The salt was dried overnight in vacuo at 55-60° C. to yield a whitecrystalline solid. Yield 6.12 g, 92.3%. Mpt 208° C.

[0728] δ (DMSO): 1.18 (3H, t), 1.28 (3H, t), 1.36 (3H, t), 2.28 (3H,s),2.78 (2H, q), 2.99 (2H, q), 3.23 (4H, t) 3.25 (3H, s), 3.55 (2H, t),3.80 (2H, t), 3.82 (2H, t), 4.51 (2H, t), 4.53 (2H, q), 7.11 (2H,d),7.47-(2H,d), 8.30 (1H,d), 8.73 (1H,d), 9.2 (1H,s), 11.90 (1H,s).

EXAMPLE 1051-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-[(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine(+) Camphor-Sulfonate Salt

[0729]

[0730] 3 g (0.006 mol) of the compound of Example 103,1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine,was charged followed by a 2-butanone/water (4% v/v) at 10 ml/g (30 mls)and warmed to reflux. 1.48 g (0.006 mol) of (+)-camphor sulphonic aciddissolved in 5 mls 2-butanone and 1 ml water was added to the refluxingsolution in <1 minute. 3.3 ml/g (10 mls) were azeotroped out and thesolution cooled with crystallisation occurring at 45° C. approximately.The slurry was cooled to 5-10° C. and granulated for 0.5 hours afterwhich it was filtered and washed with 5 ml/g (15 mls) of 2-butanone. Thesalt was dried overnight in vacuo at 55-60° C. to yield a whitecrystalline solid. (Yield 3.4 g, 77%). Mpt 222-225° C.

[0731] δ (DMSO): 0.75 (3H, s), 1.03 (3H,s), 1.18 (3H, t), 1.28 (3H, t),1.36 (3H, t), 1.20-1.40 (2H,m), 1.79-198 (3H, m), 2.2-2.3 (1H, m),2.5-2.62 (2H,m), 2.78 (2H, q), 2.99 (2H, q), 3.02 (1H,d), 3.23 (4H, t)3.25 (3H, s), 3.55 (2H, t), 3.79 (2H, t), 3.82 (2H, t), 4.51 (2H, t),4.50 (2H, q), 8.29 (1H,d), 8.73 (1H,d), 9.33 (1H,s), 11.85 (1H,s).

EXAMPLE 1061-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl]-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine(+/−)-camphor Sulfonate Salt

[0732]

[0733] 17 g (0.033 mol) of the compound of Example 103,1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine,was charged followed by ethyl alcohol at 10 ml/g (170 mls) and warmed toreflux. 7.75 g (0.035 mol) of racemic camphor sulphonic acid dissolvedin 30 mls ethyl alcohol was added to the refluxing solutioninstantaneously. The solution was allowed cool and crystallisationoccurred at 65-66° C. The slurry was cooled to 5-10° C. and granulatedfor 1 hours after which it was filtered and washed with 3 ml/g (51 mls)of ethyl alcohol. The salt was dried overnight in vacuo at 55-60° C. toyield a white crystalline solid. (Yield 22.1 g, 89.8%).

[0734] δ (DMSO): 0.75 (3H, s), 1.03 (3H,s), 1.18 (3H, t), 1.28 (3H, t),1.36 (3H, t), 1.20-1.40 (2H,m), 1.79-198 (3H, m), 2.2-2.3 (1H, m),2.5-2.62 (2H,m), 2.78 (2H, q), 2.99 (2H, q), 3.02 (1H,d), 3.23 (4H, t),3.25 (3H, s), 3.55 (2H, t), 3.79 (2H, t), 3.82 (2H, t), 4.51 (2H, t),4.50 (2H, q), 8.29 (1H,d), 8.73 (1H,d), 9.33 (1H,s), 11.85 (1H,s).

EXAMPLE 1071-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazineEthane-Sulfonate Salt

[0735]

[0736] 5 g (9.6 mmol) of the title compound of Example 102,1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine,was charged followed by a 10 ml/g (0.05 litres) Ethanol and warmed toreflux. 1.1 g (10.5 mmol) of ethane sulfonic acid diluted in 2 mlethanol was added to the refluxing solution. The slurry was cooled withcrystallisation occurring at 26-30° C. The slurry was granulatedfiltered and washed with 2 ml/g (0.01 litres) of ethanol. The salt wasdried overnight in vacuo at 55-60° C. to yield a white crystallinesolid. Yield 5.2 g, 86.1%. Mpt 205-210° C. δ (CDCl₃): 1.16 (3H, t), 1.39(3H, t), 1.41 (3H, t), 1.52 (3H, t), 2.73 (2H, q), 3.03 (2H, t), 3.09(2H,q, 3.16 (2H, t), 3.30 (3H, s), 3.35(2H, t), 3.65 (2H, t), 3.89 (2H,t), 3.90 (2H, q), 4.46 (2H, t), 4.71 (2H, q), 8.63 (1H, d), 8.71 (1H,d), 10.76 (1H, s), 11.29 (1H, s).

[0737] Biological Activity

[0738] The following Table illustrates both the in vitro activities fora range of the compounds of the invention as inhibitors of cGMP PDE₅ aswell as their selectivity for cGMP PDE₅ versus cGMP PDE₆.

[0739] The IC₅₀ measurements for cGMP PDE₅ were based upon datagenerated on human corpus cavernosum tissue and the IC₅₀ measurementsfor rod cGMP PDE6 were based upon data generated on bovine retina tissueand wherein the selectivity ratio for cGMP PDE₅ to cGMP PDE₆ quoted isbased upon IC₅₀ PDE5/IC₅₀ PDE₆. TABLE EXAMPLE IC₅₀ (nM) Selectivity (PDE5/6) 5 1.0 — 8 1.68 223.8 17 0.90 254.1 22 6.4 325.3 24 1.52 134.9 270.85 161   53 1.09 — 60 0.45 343.7

Preparation 1 3-Ethyl-1-(2-methoxyethyl)-4-nitropyrazole-5-carboxamideand Preparation 23-Ethyl-2-(2-methoxyethyl)-4-nitropyrazole-5-carboxamide

[0740]

[0741] A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (WO,9849166), (1.7 g, 8.8 mmol), 2-bromoethyl methyl ether (0.85 ml, 8.85mmol) and cesium carbonate (2.9 g, 9.0 mmol) in N,N-dimethylformamide(20 ml) was stirred at room temperature for 20 hours. The reactionmixture was concentrated under reduced pressure and the residue waspartitioned between ethyl acetate (125 ml) and brine (100 ml). Thephases were separated, and the organic layer was dried (Na₂SO₄), andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel, using ethyl acetate:methanol (97:3)as eluant to afford the title compound of preparation 1, 831 mg,

[0742] δ (DMSOd₆): 1.19 (3H, t), 2.82 (2H, q), 3.20 (3H, s), 3.68 (2H,t), 4.22 (2H, t), 8.18 (1H, s), 8.38 (1H, s).

[0743] LRMS: m/z 260 (M+18)⁺

[0744] and the title compound of preparation 2, 793 mg.

[0745] δ (CDCl₃): 1.18 (3H, t), 2.98 (2H, q), 3.22 (3H, s), 3.70 (2H,t), 4.28 (2H, t), 7.65 (1H, s), 7.94 (1H, s).

[0746] LRMS: m/z 243 (M+1)⁺

Preparation 31-(2-Methoxyethyl)-4-nitro-3-n-propylpyrazole-5-carboxamide andPreparation 42-(2-Methoxyethyl)-4-nitro-3-n-propylpyrazole-5-carboxamide

[0747]

[0748] A mixture of 4-nitro-3-n-propyl-1H-pyrazole-5-carboxamide (WO,9849166), (7.3 g, 37.0 mmol), 2-bromoethyl methyl ether (3.85 ml, 41.0mmol) and cesium carbonate (24.0 g, 74.0 mmol) in N,N-dimethylformamide(300 ml) was heated at 70° C. for 4 hours. The cooled mixture wasconcentrated under reduced pressure and the residue partitioned betweenethyl acetate (100 ml) and brine (100 ml) and the phases separated. Theaqueous layer was extracted with ethyl acetate (2×100 ml), the combinedorganic solutions dried (Na₂SO₄) and evaporated under reduced pressure.The residue was triturated with ether and the resulting precipitatefiltered and dried, to give some of the N2 isomer. The filtrate wasevaporated under reduced pressure and the residue was purified by columnchromatography on silica gel, using an elution gradient of ethylacetate:methanol (100:0 to 99:1). The product of preparation 3 wassuspended in ether, the mixture filtered and the filtrate evaporatedunder reduced pressure to afford the title compound of preparation 3,1.07 g,

[0749] δ (CDCl₃): 1.00 (3H, t), 1.74 (2H, m), 2.88 (2H, t), 3.35 (3H,s), 3.78 (2H, t), 4.47 (2H, t), 6.06 (1H, s), 7.24 (1H, s).

[0750] LRMS: m/z 257 (M+1)⁺

[0751] More of the N2 isomer (preparation 4) was also obtained to give atotal of 3.85 g.

[0752] δ (DMSOd₆): 1.04 (3H, t), 1.68 (2H, m), 2.98 (2H, t), 3.30 (3H,s), 3.79 (2H, t), 4.29 (2H, t), 5.85 (1H, s), 7.35 (1H, s).

[0753] LRMS: m/z 257 (M+1)⁺

Preparation 52-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-ethyl-4-nitropyrazole-5-carboxamide

[0754]

[0755] A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (WO,9849166), (4.9 g, 26.6 mmol), cesium carbonate (21.0 g, 64.5 mmol) and(2-bromoethoxy)-tert-butyldimethylsilane (7.0 g, 29.0 mmol) inacetonitrile (400 ml) was stirred at 80° C. for 20 hours. The cooledmixture was concentrated under reduced pressure and the residue waspartitioned between ethyl acetate (200 ml) and water (100 ml). Thelayers were separated, the organic phase washed with water (3×50 ml),dried (Na₂SO₄) and evaporated under reduced pressure. The crude productwas purified by column chromatography on silica gel, using ethyl acetateas eluant, and repeated using an elution gradient of pentane:ethylacetate (50:50 to 0:100), to give some of the desired compound.

[0756] The crude product containing both the N1 and N2 isomers wastriturated with pentane, the resulting precipitate filtered and dried toafford the title compound as a solid (1.7 g, in total)

[0757] δ (CDCl₃): −0.05 (6H, s), 0.81 (9H, s), 1.28 (3H, t), 3.08 (2H,q), 4.03 (2H, t), 4.24 (2H, t), 5.80 (1H, s), 7.34 (1H, s).

[0758] LRMS: m/z 343 (M+1)⁺

Preparation 6 Tert-Butyl 3-iodo-1-azetidinecarboxylate

[0759]

[0760] A mixture of tert-butyl3-[(methylsulphonyl)oxy]-1-azetidinecarboxylate (Synlett; 1998; 379),(5.0 g, 19.9 mmol), and potassium iodide (16.5 g, 99.4 mmol) inN,N-dimethylformamide (25 ml), was heated at 100° C. for 42 hours. Thecooled mixture was partitioned between water and ethyl acetate, and thelayers separated. The organic phase was dried (MgSO₄), concentratedunder reduced pressure and the residue azeotroped with xylene. The crudeproduct was purified by column chromatography on silica gel usingdichloromethane as eluant, to give the title compound, 3.26 g.

[0761] δ (CDCl₃): 1.43 (9H, s), 4.28 (2H, m), 4.46 (1H, m), 4.62 (2H,m),

[0762] LRMS: m/z 284 (M+1)⁺

Preparation 7 Tert-Butyl3-[3-(aminocarbonyl)-5-ethyl-4-nitropyrazol-1-yl-1-azetidinecarboxylate

[0763]

[0764] A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (WO,9849166), (6.59 g, 35.8 mmol), cesium carbonate (12.25 g, 37.6 mmol),and the title compound of preparation 6 (10.3 g, 37.6 mmol) inN,N-dimethylformamide (60 ml) was heated at 60° C. for 3 days. Thecooled reaction was poured into 2% aqueous sodium bicarbonate solution(250 ml), and extracted with ethyl acetate (1×230 ml, 1×100 ml). Thecombined organic extracts were dried (MgSO₄) and evaporated underreduced pressure. The residual oil was purified by column chromatographyon silica gel, using an elution gradient of ethyl acetate:pentane (50:50to 100:0) to give the N1-isomer (5.0 g) and the title compound ofpreparation 7, 4.1 g.

[0765] δ (CDCl₃): 1.25 (3H, t), 1.46 (9H, s), 2.96 (2H, q), 4.37 (2H,m), 4.44 (2H, m), 5.06 (1H, m), 5.82 (1H, s), 6.63 (1H, s).

PREPARATION 8 Benzyl2-[3-(aminocarbonyl)-5-ethyl-4-nitropyrazol-1-yl]ethyl(methyl)carbamate

[0766]

[0767] Obtained (25%) from 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide(WO, 9849166), and 2-[(benzyloxy)carbonyl](methyl)amino]ethylmethanesulphonate (J.Med.Chem. 37; 23; 1994; 3977) following a similarprocedure to that described in preparation 7.

[0768] δ (CDCl₃): (rotamers in 0.42:0.58 ratio) 1.03 and 1.20 (3H, t),2.69 and 2.87 (2H, q), 2.80 and 2.92 (3H, s), 3.72 (2H, m), 4.20 and4.33 (2H, t), 5.02 and 5.14 (2H, s), 5.86 (1H, m), 7.35 (6H, m).

Preparation 9 4-Amino-3-ethyl-2-(2-methoxyethyl)pyrazole-5-carboxamide

[0769]

[0770] A mixture of the title compound from preparation 2 (500 mg, 2.07mmol) and 10% palladium on charcoal (50 mg) in ethanol (20 ml) washydrogenated at 50 psi and room temperature for 18 hours. The reactionmixture was filtered through Arbocel®, and the filtrate evaporated underreduced pressure to afford the title compound as a white solid.

[0771] δ (DMSOd₆): 1.03 (3H, t), 2.57 (2H, q), 3.20 (3H, s), 3.63 (2H,t), 4.09 (2H, t), 4.39 (2H, s), 6.90 (1H, s), 7.01 (1H, s).

[0772] LRMS: m/z 213 (M+1)+

Preparations 10 to 12

[0773] The compounds of the general structure:

[0774] were prepared from the corresponding nitropyrazole, following asimilar procedure to that described in preparation 9. Prep Yield No. R₁R₂ (%) m/z ¹Hnmr 10

(CH₂)₂CH₃ 95 227 (M + 1)⁺ δ(CDCl₃): 0.98(3H, t), 1.60 (2H, m), 2.47(2H,t), 3.30(3H, s), 3.74(2H, t), 3.94(2H, s), 4.15(2H, t), 5.20(1H, s),6.58 (1H, s). 11

CH₂CH₃ 335 (M + 23)⁺ δ(CDCl₃): −0.03(6H, s), 0.85 (9H, s), 1.18(3H, t),2.63(2H, q), 3.94(4H, m), 4.08(2H, t), 5.15(1H, s), 6.57(1H, s). 12

CH₂CH₃ 73 δ(CDCl₃): 1.14(3H, t), 1.46 (9H, s), 2.55(2H, q), 3.98(2H, s),4.29(2H, m), 4.40(2H, m), 4.94(1H, m), 5.23(1H, s), 6.64 (1H, s).

Preparation 13 Benzyl2-[4-amino-3-(aminocarbonyl)-5-ethylpyrazol-1-yl]ethyl(methyl)carbamate

[0775]

[0776] A mixture of the title compound of preparation 8 (1.92 g, 5.28mmol), iron powder (3.04 g) and water (2.5 ml) in acetic acid (50 ml)was stirred at room temperature for 25 minutes. The reaction mixture wasfiltered through Arbocel®, and the filtrate poured slowly into saturatedsodium bicarbonate solution (400 ml). The pH of the solution wasadjusted to 8 using solid sodium carbonate, and this solution was thenextracted with ethyl acetate (2×350 ml). The combined organic extractswere dried (MgSO₄) and evaporated under reduced pressure to afford thetitle compound, 1.5 g.

[0777] δ (CDCl₃): (rotamers in a 0.46:0.54 ratio), 1.00 and 1.14 (3H,t), 2.38 and 2.50 (2H, q), 2.68 and 2.80 (3H, s), 3.63 (2H, m), 3.95(2H, s), 4.04 and 4.17 (2H, t), 5.10 and 5.14 (2H, s), 5.14 (1H, s),6.53 (1H, s), 7.36 (5H, m).

Preparation 14 4-Amino-3-ethyl-1-(2-methoxyethyl)pyrazole-5-carboxamide

[0778]

[0779] Obtained from the title compound of preparation 1 (95%), using asimilar procedure to that described in preparation 9, and afterpurification by column chromatography using dichloromethane:methanol(90:10) as eluant.

[0780] δ (CDCl₃): 1.26 (3H, t), 2.58 (2H, q), 3.37 (3H, s), 3.60 (2H,s), 3.82 (2H, t), 4.50 (2H, t).

[0781] LRMS: m/z 213 (M+1)⁺

Preparation 154-Amino-1-(2-methoxyethyl)-3-n-propylpyrazole-5-carboxamide

[0782]

[0783] Obtained as a solid (99%) from the title compound of preparation3, using the procedure described in preparation 9.

[0784] δ (CDCl₃): 0.95 (3H, t), 1.63 (2H, m), 2.48 (2H, t), 3.30 (3H,s), 3.78 (2H, t), 4.46 (2H, t).

[0785] LRMS: m/z 227 (M+1)⁺

Preparation 16

[0786] Pyridine-2-amino-5-sulphonic Acid

[0787] 2-Aminopyridine (80 g, 0.85 mol) was added portionwise over 30minutes to oleum (320 g) and the resulting solution heated at 140° C.for 4 hours. On cooling, the reaction was poured onto ice (200 g) andthe mixture stirred in an ice/salt bath for a further 2 hours. Theresulting suspension was filtered, the solid washed with ice water (200ml) and cold IMS (200 ml) and dried under suction to afford the titlecompound as a solid, 111.3 g.

[0788] LRMS: m/z 175 (M+1)⁺

Preparation 17 Pyridine-2-amino-3-bromo-5-sulphonic Acid

[0789]

[0790] Bromine (99 g, 0.62 mol) was added dropwise over an hour, to ahot solution of the title compound of preparation 16 (108 g, 0.62 mol)in water (600 ml) so as to maintain a steady reflux. Once the additionwas complete the reaction was cooled and the resulting mixture filtered.The solid was washed with water and dried under suction to afford thetitle compound, 53.4 g.

[0791] δ (DMSOd₆, 300 MHz): 8.08 (1H, s), 8.14 (1H, s).

[0792] LRMS: m/z 253 (M)⁺

Preparation 18

[0793] Pyridine-3-bromo-2-chloro-5-sulphonyl Chloride

[0794] A solution of sodium nitrite (7.6 g, 110.0 mmol) in water (30 ml)was added dropwise to an ice-cooled solution of the title compound ofpreparation 17 (25.3 g, 100.0 mmol) in aqueous hydrochloric acid (115ml, 20%), so as to maintain the temperature below 6° C. The reaction wasstirred for 30 minutes at 0° C. and for a further hour at roomtemperature. The reaction mixture was evaporated under reduced pressureand the residue dried under vacuum at 70° C. for 72 hours. A mixture ofthis solid, phosphorus pentachloride (30.0 g, 144.0 mmol) and phosphorusoxychloride (1 ml, 10.8 mmol) was heated at 125° C. for 3 hours, andthen cooled. The reaction mixture was poured onto ice (100 g) and theresulting solid filtered, and washed with water. The product wasdissolved in dichloromethane, dried (MgSO₄), and evaporated underreduced pressure to afford the title compound as a yellow solid, 26.589.

[0795] δ (CDCl₃, 300 MHz): 8.46 (1H, s), 8.92 (1H, s).

Preparation 193-Bromo-2-chloro-5-(4-ethylpiperazin-1-ylsulphonyl)pyridine

[0796]

[0797] A solution of 1-ethylpiperazine (11.3 ml, 89.0 mmol) andtriethylamine (12.5 ml, 89.0 mmol) in dichloromethane (150 ml) was addeddropwise to an ice-cooled solution of the title compound of preparation18 (23.09, 79.0 mmol) in dichloromethane (150 ml) and the reactionstirred at 0° C. for an hour. The reaction mixture was concentratedunder reduced pressure and the residual brown oil was purified by columnchromatography on silica gel, using an elution gradient ofdichloromethane:methanol (99:1 to 97:3) to afford the title compound asan orange solid, 14.5 g.

[0798] δ (CDCl₃, 300 MHz): 1.05 (3H, t), 2.42 (2H, q), 2.55 (4H, m),3.12 (4H, m), 8.24 (1H, s), 8.67 (1H, s).

Preparation 203-Bromo-2-chloro-5-(4-methylpiperazin-1-ylsulphonyl)pyridine

[0799]

[0800] N-Methylpiperazine (7.65 ml, 69.0 mmol) was added dropwise to asolution of the title compound of preparation 18 (10.0 g, 34.5 mmol) inethanol (200 ml), and the reaction stirred at room temperature for 3hours. The mixture was concentrated under reduced pressure and theresidue partitioned between dichloromethane (200 ml) and water (100 ml)and the layers separated. The organic phase was dried (Na₂SO₄), andevaporated under reduced pressure to afford the title compound, 10.53 g,as a yellow solid.

[0801] δ (CDCl₃): 2.28 (3H, s), 2.51 (4H, m), 3.14 (4H, m), 8.24 (1H,s), 8.67 (1H, s).

Preparation 213-Bromo-2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridine

[0802]

[0803] A mixture of the title compound of preparation 19 (6.60 g, 17.9mmol) and sodium ethoxide (6.099, 89.55 mmol) in ethanol (100 ml) washeated under reflux for 18 hours, then cooled. The reaction mixture wasconcentrated under reduced pressure, the residue partitioned betweenwater (100 ml) and ethyl acetate (100 ml), and the layers separated. Theaqueous phase was extracted with ethyl acetate (2×100 ml), the combinedorganic solutions dried (MgSO₄) and evaporated under reduced pressure toafford the title compound as a brown solid, 6.41 g.

[0804] Found: C, 41.27; H, 5.33; N, 11.11. C₁₃H₂₀BrN₃O₃S requires C,41.35; H, 5.28; N, 10.99%.

[0805] δ (CDCl₃, 300 MHz): 1.06 (3H, t), 1.48 (3H, t), 2.42 (2H, q),2.56 (4H, m), 3.09 (4H, m), 4.54 (2H, q), 8.10 (1H, s), 8.46 (1H, s).

[0806] LRMS: m/z 378, 380 (M+1)⁺

Preparation 223-Bromo-2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridine

[0807]

[0808] A mixture of the title compound of preparation 20 (10.09, 39.1mmol), potassium bis(trimethylsilyl)amide (5.92 g, 29.7 mmol) andethanol (3.5 ml) in tetrahydrofuran (150 ml) was stirred at roomtemperature for 24 hours. The reaction mixture was concentrated underreduced pressure and the residue partitioned between ethyl acetate (150ml) and brine (50 ml). The layers were separated, and the organic phasedried (Na₂SO₄), filtered and evaporated under reduced pressure, toafford the title compound, 9.1 g.

[0809] δ (CDCl₃): 1.44 (3H, t), 2.29 (3H, s), 2.51 (4H, m), 3.08 (4H,m), 4.54 (2H, q), 8.10 (1H, s), 8.44 (1H, s).

[0810] LRMS: m/z 365 (M+1)⁺

Preparation 23 Pyridine2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)-3-carboxylic Acid EthylEster

[0811]

[0812] A mixture of the title compound of preparation 21 (6.40 g, 16.92mmol), triethylamine (12 ml, 86.1 mmol), and palladium (0)tris(triphenylphosphine) in ethanol (60 ml) was heated at 100° C. and200 psi, under a carbon monoxide atmosphere, for 18 hours, then cooled.The reaction mixture was evaporated under reduced pressure and theresidue purified by column chromatography on silica gel, using anelution gradient of dichloromethane:methanol (100:0 to 97:3) to affordthe title compound as an orange oil, 6.29.

[0813] δ (CDCl₃, 300 MHz): 1.02 (3H, t), 1.39 (3H, t), 1.45 (3H, t),2.40 (2H, q), 2.54 (4H, m), 3.08 (4H, m), 4.38 (2H, q), 4.55 (2H, q),8.37 (1H, s), 8.62 (1H, s).

[0814] LRMS: m/z 372 (M+1)⁺

Preparation 24 Pyridine2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-3-carboxylic Acid EthylEster

[0815]

[0816] Obtained (85%) as an orange solid, from the title compound ofpreparation 22 using a similar procedure to that described inpreparation 23.

[0817] δ (CDCl₃): 1.40 (3H, t), 1.46 (3H, t), 2.28 (3H, s), 2.50 (4H,m), 3.09 (4H, m), 4.40 (2H, q), 4.57 (2H, q), 8.40 (1H, s), 8.63 (1H,s).

[0818] LRMS: m/z 358 (M+1)⁺

Preparation 25 Pyridine2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)-3-carboxylic Acid

[0819]

[0820] A mixture of the title compound of preparation 23 (4.96 g, 13.35mmol) and aqueous sodium hydroxide solution (25 ml, 2N, 50.0 mmol) inethanol (25 ml) was stirred at room temperature for 2 hours. Thereaction mixture was concentrated under reduced pressure to half it'svolume, washed with ether and acidified to pH 5 using 4N hydrochloricacid. The aqueous solution was extracted with dichloromethane (3×30 ml),the combined organic extracts dried (MgSO₄) and evaporated under reducedpressure to afford the title compound as a tan coloured solid, 4.02 g.

[0821] δ (DMSOd₆, 300 MHz): 1.18 (3H, t), 1.37 (3H, t), 3.08 (2H, q),3.17-3.35 (8H, m), 4.52 (2H, q), 8.30 (1H, s), 8.70 (1H, s).

Preparation 26 Pyridine2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-3-carboxylic AcidHydrochloride

[0822]

[0823] Sodium hydroxide solution (21 ml, 2M, 42.0 mmol) was added to asolution of the title compound of preparation 24 (7.57 g, 21.0 mmol) indioxan (150 ml) and the reaction stirred at room temperature for 18hours. The mixture was neutralised using hydrochloric acid, the dioxanremoved under reduced pressure and the remaining aqueous solutionacidified to pH 2, using hydrochloric acid. The solution was evaporatedunder reduced pressure, the residue re-suspended in hot ethanol,filtered, and the filtrate re-evaporated to afford the title compound,5.46 g.

[0824] δ (DMSOd₆): 1.37 (3H, t), 2.50 (4H, m), 2.72 (3H, s), 3.13-3.39(4H, m), 4.53 (2H, q), 8.30 (1H, s), 8.75 (1H, s).

[0825] LRMS: m/z 330 (M+1)⁺

Preparation 274-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-(2-methoxyethyl)pyrazole-5-carboxamide

[0826]

[0827] Oxalyl chloride (500 ml, 5.73 mmol) was added dropwise to anice-cooled solution of the title compound of preparation 26 (522 mg,1.43 mmol) and N,N-dimethylformamide (1 drop) in dichloromethane (20ml), and the reaction stirred for 2 hours. The mixture was concentratedunder reduced pressure and azeotroped several times with dichloromethaneto give the intermediate acid chloride. A solution of this product indichloromethane (20 ml) was added to a solution of the title compound ofpreparation 9 (250 mg, 1.18 mmol) and triethylamine (500 ml, 3.18 mmol)in dichloromethane (20 ml), and the reaction stirred at room temperaturefor 18 hours. The mixture was washed with water, dried (Na₂SO₄) andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel, using an elution gradient ofdichloromethane:methanol (100:0 to 95:5) to afford the title compound,428 mg.

[0828] δ (CDCl₃): 1.20 (3H, t), 1.59 (3H, t), 2.28 (3H, s), 2.50 (4H,m), 2.95 (2H, m), 3.10 (4H, m), 3.36 (3H, s), 3.80 (2H, t), 4.25 (2H,t), 4.78 (2H, q), 5.26 (1H, s), 6.65 (1H, s), 8.65 (1H, s), 8.85 (1H,s), 10.51 (1H, s).

[0829] LRMS: m/z 524 (M+1)⁺

Preparation 284-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-2-(2-methoxyethyl)-3-n-propylpyrazole-5-carboxamide

[0830]

[0831] The title compound was obtained as a white solid (79%), from thetitle compounds from preparation 10 and 26, following the proceduredescribed in preparation 27.

[0832] δ (CDCl₃): 0.92 (3H, t), 1.58 (5H, m), 2.24 (3H, s), 2.47 (4H,m), 2.90 (2H, t), 3.10 (4H, m), 3.35 (3H, s), 3.78 (2H, t), 4.23 (2H,t), 4.78 (2H, q), 5.42 (1H, br s), 6.68 (1H, brs), 8.62 (1H, d), 8.82(1H, d), 10.48 (1H, s).

[0833] LRMS: m/z 538 (M+1)⁺

Preparation 294-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-(2-methoxyethyl)Pyrazole-5-carboxamide

[0834]

[0835] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.26g, 27.4 mmol) was added to a solution of the title compounds frompreparation 25 (7.25 g, 21.1 mmol), and preparation 9 (4.45 g, 20.9mmol), 1-hydroxybenzotriazole hydrate (3.71 g, 27.4 mmol), andN-diisopropylethylamine (10.96 ml, 63.3 mmol) in dichloromethane (70ml), and the reaction stirred for 18 hours. The reaction mixture wasdiluted with dichloromethane (100 ml), washed with water (100 ml),saturated aqueous sodium bicarbonate solution (100 ml), and brine (100ml), dried (MgSO₄), and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol (100:0 to 95:5) to give thetitle compound as a foam, 10.05 g.

[0836] δ (CDCl₃): 1.03 (3H, t), 1.20 (3H, t), 1.58 (3H, t), 2.40 (2H,q), 2.54 (4H, m), 2.95 (2H, q), 3.10 (4H, m), 3.37 (3H, s), 3.80 (2H,t), 4.26 (2H, t), 4.78 (2H, q), 5.27 (1H, s), 6.66 (1H, s), 8.65 (1H,s), 8.85 (1H, s), 10.51 (1H, s).

[0837] LRMS: m/z 538 (M+1)⁺

Preparation 304-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-2-(2-methoxyethyl)-3-n-propylpyrazole-5-carboxamide

[0838]

[0839] N-Diisopropylethylamine. (0.92 ml, 5.3 mmol) was added to asolution of the title compounds from preparation 25 (1.0 g, 2.65 mmol),and preparation 10 (600 mg, 2.65 mmol), 1-hydroxybenzotriazole hydrate(465 mg, 3.45 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (660 mg, 3.45 mmol) in dichloromethane (20 ml), and thereaction stirred for 18 hours. The reaction mixture was washed withbrine, dried (MgSO₄), and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol (100:0 to 95:5) to affordthe title compound, 740 mg.

[0840] δ (CDCl₃): 0.94 (3H, t), 1.03 (3H, t), 1.59 (5H, m), 2.40 (2H,q), 2.54 (4H, m), 2.92 (2H, t), 3.11 (4H, m), 3.37 (3H, s), 3.80 (2H,t), 4.25 (2H, t), 4.78 (2H, q), 5.26 (1H, s), 6.66 (1H, s), 8.65 (1H,s), 8.83 (1H, s), 10.48 (1H, s).

[0841] LRMS: m/z 552 (M+1)⁺

Preparation 312-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethylpyrazole-5-carboxamide

[0842]

[0843] Obtained as a white solid (67%) from the title compounds ofpreparations 25 and 0.11 following a similar procedure to that describedin preparation 27.

[0844] δ (CDCl₃): 0.00 (6H, s), 0.85 (9H, s), 1.04 (3H, t), 1.22 (3H,t), 1.57 (3H, t), 2.40 (2H, q), 2.53 (4H, m), 2.94 (2H, q), 3.10 (4H,m), 4.02 (2H, t), 4.19 (2H, t), 4.78 (2H, q), 5.39 (1H, s), 6.66 (1H,s), 8.64 (1H, s), 8.83 (1H, s), 10.49 (1H, s).

[0845] LRMS: m/z 638 (M+1)⁺

Preparation 32 Benzyl2-{3-(aminocarbonyl)-4-[({2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulphonyl]-3-pyridinyl}carbonyl)amino]-5-ethylpyrazol-1-yl}ethyl(methyl)carbamate

[0846]

[0847] Triethylamine (1.0 ml, 7.2 mmol) was added to a solution of thetitle compounds from preparation 25 (1.5 g, 4.5 mmol), and preparation13 (1.7 g, 4.95 mmol), 1-hydroxybenzotriazole hydrate (833 mg, 5.44mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.28 g, 6.68 mmol) in dichloromethane (50 ml), and the reaction stirredfor 3 days at room temperature. The reaction mixture was concentratedunder reduced pressure and the residue partitioned between saturatedaqueous sodium bicarbonate solution and ethyl acetate, and the layersseparated. The aqueous phase was extracted with ethyl acetate (2×50 ml),and the combined organic solutions, dried (MgSO₄), and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol (95:5) aseluant to afford the title compound, 3.0 g.

[0848] δ (CDCl₃): 1.00-1.20 (6H, m), 1.58 (3H, t), 2.40 (2H, q), 2.54(4H, m), 2.70-2.91 (5H, m), 3.10 (4H, m), 3.70 (2H, m), 4.16-4.32 (2H,m), 4.79 (2H, q), 5.12 (2H, m), 5.24 (1H, s), 6.62 (1H, s), 7.37 (5H,m), 8.64 (1H, s), 8.82 (1H, s), 10.50 (1H, s).

Preparation 332-(1-tert-Butyloxycarbonylazetidin-3-yl)-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonylpyridin-3-ylcarboxamido]-3-ethylyrazole-5-carboxamide

[0849]

[0850] The title compound was obtained (72%) from the title compoundsfrom preparation 25 and preparation 12, following a similar procedure tothat described in preparation 32.

[0851] δ (CDCl₃): 1.01 (3H, t), 1.19 (3H, t), 1.47 (9H, s), 1.58 (3H,t), 2.40 (2H, q), 2.54 (4H, m), 2.86 (2H, q), 3.10 (4H, m), 4.38 (2H,m), 4.41 (2H, m), 4.79 (2H, q), 5.10 (1H, m), 5.30 (1H, br s), 6.77 (1H,br s), 8.63 (1H, d), 8.82 (1H, d), 10.57 (1H, s).

Preparation 344-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-1H-3-ethylpyrazole-5-carboxamide

[0852]

[0853] A solution of 3-ethyl-1H-pyrazole-5-carboxamide (WO, 9849166)(9.2 g, 59.8 mmol) in N,N-dimethylformamide (60 ml) was added to asolution of the title compound from preparation 25 (21.7 g, 62.9 mmol),1-hydroxybenzotriazole hydrate (10.1 g, 66.0 mmol) and triethylamine(13.15 ml, 94.3 mmol) in dichloromethane (240 ml).1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.26 g,69.2 mmol) was added and the reaction stirred at room temperature for 6hours. The dichloromethane was removed under reduced pressure, theremaining solution poured into ethyl acetate (400 ml), and this mixturewashed with aqueous sodium bicarbonate solution (400 ml). The resultingcrystalline precipitate was filtered, washed with ethyl acetate anddried under vacuum, to afford the title compound, as a white powder, 22g.

[0854] δ (CDCl₃+1 drop DMSOd₆) 0.96 (3H, t), 1.18 (3H, t), 1.50 (3H, t),2.25-2.56 (6H, m), 2.84 (2H, q), 3.00 (4H, m), 4.70 (2H, q), 5.60 (1H,br s), 6.78 (1H, br s), 8.56 (1H, d), 8.76 (1H, d), 10.59 (1H, s),12.10-12.30 (1H, s).

[0855] LRMS: m/z 480 (M+1)⁺

Preparation 354-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-1H-3-ethylpyrazole-5-carboxamide

[0856]

[0857] Oxalyl chloride (9.5 ml, 108 mmol) was added dropwise to anice-cold solution of the title compound from preparation 26 (10.0 g,27.0 mmol) and N,N-dimethylformamide (160%1) in dichloromethane (150ml), and once addition was complete, the reaction was stirred at roomtemperature for 5½ hours. The mixture was evaporated under reducedpressure and the residue azeotroped with toluene, to give a yellowsolid.

[0858] Triethylamine (11.2 ml, 81.0 mmol) was added to a solution of theintermediate acid chloride (10.5 g, 27.3 mmol) and4-amino-3-ethyl-1H-pyrazole-5-carboxamide (WO, 9849166), (4.2 g, 27.3mmol) in dichloromethane (150 ml), and the reaction stirred at roomtemperature for 18 hours. The mixture was diluted with water, and thelayers separated. The aqueous phase was extracted with dichloromethane(2×), and the combined organic solutions dried (Na₂SO₄) and evaporatedunder reduced pressure. The crude product was triturated with ether, andthe resulting solid filtered to give the title compound, 10.1 g.

[0859] δ (CDCl₃) 1.21 (3H, t), 1.59 (3H, t), 2.26 (3H, s), 2.50 (4H, m),2.94 (2H, q), 3.10 (4H, m), 4.79 (2H, q), 5.50 (1H, br s), 6.80 (1H, brs), 8.64 (1H, d), 8.84 (1H, d), 10.65 (1H, s).

Preparation 362-iso-Butyl-4-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethylpyrazole-5-carboxamide

[0860]

[0861] 1-Bromo-2-methylpropane (187 μl, 1.72 mmol) was added to asolution of the title compound from preparation 34 (750 mg, 1.56 mmol)and cesium carbonate (1.12 g, 3.44 mmol) in N,N-dimethylformamide (15ml) and the reaction stirred at 60° C. for 18 hours. The cooled mixturewas partitioned between water and ethyl acetate, and the layersseparated. The organic layer was dried (MgSO₄), concentrated underreduced pressure and azeotroped with toluene to give a solid. Thisproduct was recrystallised from ether, to afford the title compound as awhite solid, 152 mg.

[0862] δ (CDCl₃): 0.96 (6H, d), 1.02 (3H, t), 1.19 (3H, t), 1.58 (3H,t), 2.26 (1H, m), 2.40 (2H, q), 2.52 (4H, m), 2.94 (2H, q), 3.10 (4H,m), 3.88 (2H, d), 4.78 (2H, q), 5.25 (1H, s), 6.65 (1H, s), 8.64 (1H,d), 8.83 (1H, d), 10.54 (1H, s).

[0863] LRMS: m/z 536 (M+1)⁺

Preparations 37 to 41

[0864] The following tabulated compounds of the general formula:

[0865] were prepared from the title compound from preparation 34 and theappropriate bromide, following a similar procedure to that described inpreparation 36. Prep Yield m/z no R1 R10 (%) (M + 1)⁺ ¹Hnmr 37

Et 48 534 δ(CDCl₃): 0.42(2H, m), 0.63(2H, m), 1.02(3H, t), 1.20(3H, t),1.58 (3H, t), 2.40(2H, q), 2.54(4H, m), 2.95(2H, q), 3.10(4H, m),3.47(1H, m), 3.98(2H, d), 4.78(2H, q), 5.22 (1H, br s), 6.65(1H, br s),8.63(1H, s), 8.83(1H, s), 10.57(1H, s). 38

Et 51 548 δ(CDCl₃): 1.01(3H, t), 1.18(3H, m), 1.58(3H, t), 1.80-1.97(4H,m), 2.08(2H, m), 2.40(2H, q), 2.54(4H, m), 2.80-2.97(3H, m), 3.10(4H,m), 4.10(2H, d), 4.78(2H, q), 5.11(1H, br s), 6.63(1H, br s), 8.63(1H,s), 8.83(1H, s), 10.53(1H, s). 39

Et 51 536 δ(CDCl₃): 0.83(3H, t). 1.03(3H, t), 1.21(3H, t), 1.48(3H, d),1.60(3H, t), 1.80(1H, m), 2.00(1H, m), 2.40 (2H, q), 2.55(4H, m),2.90(2H, m), 3.12(4H, m), 4.24(1H, m), 4.78 (2H, q), 5.22(1H, br s),6.70(1H, br s), 8.64(1H, s), 8.83(1H, s), 10.50 (1H, s). 40

Me 44 522 δ(CDCl₃): 0.96(6H, d), 1.17(3H, t), 1.59(3H, t), 2.27(4H, m),2.48(4H, m), 2.91(2H, q), 3.09(4H, m), 3.88 (2H, d), 4.78(2H, q),5.24(1H, br s), 6.67(1H, br s), 8.65(1H, m), 8.84 (1H, m), 10.54(1H, s).41

Me 33 546 δ(CDCl₃): 1.19(3H, t), 1.58(3H, m), 1.87(4H, m), 2.10(2H, m),2.26 (3H, s), 2.48(4H, m), 2.92(3H, m), 3.10(4H, m), 4.10(2H, d),4.79(2H, q), 5.24(1H, br s), 6.65(1H, br s), 8.64(1H, d), 8.84(1H, d),10.55 (1H, s).

Preparation 424-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-(tetrahydrofuran-2-yl)methylpyrazole-5-carboxamide

[0866]

[0867] Cesium carbonate (1.63 g, 5.0 mmol) was added to an ice-coldsolution of the title compound from preparation 34 (2.0 g, 4.18 mmol) inN,N-dimethylformamide (40 ml), and the solution stirred for 30 minutes.Tetrahydrofuryl bromide (0.6 ml, 5.28 mmol) was added, and the reactionheated at 60° C. for 72 hours. The cooled mixture was evaporated underreduced pressure, and the residue partitioned between water anddichloromethane. The phases were separated, and the organic layer wasdried (MgSO₄), and evaporated under reduced pressure. The crude productwas purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (100:0 to 95:5) to afford the titlecompound, 1.20 g.

[0868] δ (CDCl₃): 1.01 (3H, t), 1.18 (3H, t), 1.58 (3H, t), 1.70-2.12(4H, m), 2.40 (2H, q), 2.54 (4H, m), 2.97 (2H, m), 3.10 (4H, m),3.74-3.94 (2H, m), 4.16 (2H, m), 4.32 (1H, m), 4.78 (2H, q), 5.32 (1H,br s), 6.64 (1H, br s), 8.63 (1H, s), 8.82 (1H, s), 10.50 (1H, s).

[0869] LRMS: m/z 564 (M+1)⁺

Preparation 43 2-Methoxy-1-methylethyl Methanesulphonate

[0870]

[0871] Methanesulphonyl chloride (2.86 ml, 36.9 mmol) was added dropwiseto an ice-cooled solution of 1-methoxy-2-propanol (3 ml, 30.7 mmol) andtriethylamine (10.27 ml, 73.7 mmol) in dichloromethane (150 ml), and thereaction stirred at room temperature for 18 hours. The mixture waswashed with water, then 2M hydrochloric acid, dried (MgSO₄) andevaporated under reduced pressure to give the title compound as a yellowoil, 5.24 g.

[0872] δ (CDCl₃): 1.39 (3H, d), 3.03 (3H, s), 3.39 (3H, s), 3.46 (2H,m), 4.88 (1H, m).

[0873] LRMS: m/z 186 (M+18)⁺

Preparation 44 2-[(tert-Butoxycarbonyl)(methyl)amino]ethylMethanesulphonate

[0874]

[0875] Methanesulphonyl chloride (2.98 ml, 38.6 mmol) was added to anice-cold solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (Synth.Commun. 1993; 23(17); 2443) (4.5 g, 25.7 mmol) in pyridine (40 ml), andthe reaction stirred for 2 hours. The solution was poured into water(150 ml), and extracted with ethyl acetate (2×50 ml). The combinedorganic extracts were washed with 10% aqueous citric acid solution,dried (MgSO₄) and evaporated under reduced pressure. The crude productwas purified by column chromatography on silica gel using an elutiongradient of ethyl acetate:pentane (34:66 to 40:60) to give the titlecompound, 1.0 g.

[0876] δ (CDCl₃): 1.46 (9H, s), 2.96 (3H, s), 3.02 (3H, s), 3.56 (2H,m), 4.34 (2H, m).

Preparation 454-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-(1-methyl-2-methoxyethyl)pyrazole-5-carboxamide

[0877]

[0878] Sodium hydride (64 mg, 60% dispersion in mineral oil, 1.6 mmol)was added to a solution of the title compound from preparation 34 (700mg, 1.46 mmol) in tetrahydrofuran (10 ml), and the solution stirred for10 minutes. The title compound from preparation 43 (270 mg, 1.60 mmol)was added and the reaction stirred at 60° C. for 3 days. The cooledmixture was partitioned between ethyl acetate and aqueous sodiumbicarbonate solution, and the phases separated. The aqueous layer wasextracted with ethyl acetate, the combined organic solutions dried(MgSO₄) and evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel using dichloromethane:methanol(98:2) as eluant to afford the title compound as a white foam, 310 mg.

[0879] δ (CDCl₃): 1.02 (3H, t), 1.22 (3H, m), 1.50 (3H, d), 1.59 (3H,t), 2.40 (2H, q), 2.55 (4H, m), 2.92 (2H, m), 3.10 (4H, m), 3.30 (3H,s), 3.60 (1H, m), 3.78 (1H, m), 4.57 (1H, m), 4.78 (2H, q), 5.25 (1H, brs), 6.68 (1H, br s), 8.64 (1H, s), 8.83 (1H, s), 10.48 (1H, s).

[0880] LRMS: m/z 552 (M+1)⁺

Preparation 462-(1-tert-Butoxycarbonylpiperidin-4-yl)-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethylpyrazole-5-carboxamide

[0881]

[0882] The title compound was obtained (43%), from the title compoundfrom preparation 34 and tert-butyl4-[(methylsulphonyl)oxy]-1-piperidinecarboxylate (WO, 9319059),following the procedure described in preparation 45.

[0883] δ (CDCl₃): 1.02 (3H, t), 1.23 (3H, t), 1.49 (9H, s), 1.57 (3H,m), 1.93 (2H, m), 2.16 (2H, m), 2.40 (2H, q), 2.54 (4H, m), 2.82-2.97(4H, m), 3.10 (4H, m), 4.30 (3H, m), 4.79 (2H, q), 5.23 (1H, s), 6.65(1H, s), 8.63 (1H, d), 8.82 (1H, d), 10.57 (1H, s).

Preparation 472-{2-[(tert-Butoxycarbonyl)(methyl)amino]ethyl}-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethylpyrazole-5-carboxamide

[0884]

[0885] The title compound was prepared from the title compounds frompreparation 34 and 44 following a similar procedure to that described inpreparation 45. The crude product was purified by column chromatographyon silica gel using ethyl acetate:diethylamine (95:5) as eluant to givethe title compound, 30%.

[0886] δ (CDCl₃): 1.02 (3H, t), 1.20 (3H, t), 1.46 (9H, s), 1.57 (3H,t), 2.40 (2H, q), 2.53 (4H, m), 2.88 (3H, s), 3.10 (4H, m), 3.58 (1H,m), 3.64 (2H, m), 4.22 (2H, m), 4.30 (1H, m), 4.79 (2H, q), 5.24 (1H,s), 6.65 (1H, s), 8.62 (1H, d), 8.82 (1H, d), 10.53 (1H, s).

Preparation 484-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-[2-(pyrazole-1-yl)ethyl]pyrazole-5-carboxamide

[0887]

[0888] Sodium hydride (88 mg, 60% dispersion in mineral oil, 2.19 mmol)was added to an ice-cold solution of the title compound from preparation34 (1.0 g, 2.09 mmol) in tetrahydrofuran (25 ml), and the solutionstirred for an hour. 1-(2-Chloroethyl)pyrazole (WO 9849166) (410 mg,3.14 mmol) was added and the reaction heated under reflux for 18 hours.The cooled mixture was concentrated under reduced pressure and theresidue partitioned between water and ethyl acetate and the layersseparated. The aqueous phase was extracted with ethyl acetate, thecombined organic solutions dried (MgSO₄) and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using an elution gradient of dichloromethane:methanol (100:0to 90:10) to give the title compound, 300 mg.

[0889] δ (CDCl₃): 1.02 (6H, m), 1.58 (3H, t), 2.40 (2H, q), 2.56 (6H,m), 3.10 (4H, m), 4.50 (2H, t), 4.63 (2H, t), 4.78 (2H, q), 6.20 (1H,m), 7.06 (1H, m), 7.58 (1H, m), 8.63 (1H, d), 8.80 (1H, d), 10.46 (1H,s).

Preparation 494-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-(4-nitrophenyl)pyrazole-5-carboxamide

[0890]

[0891] Sodium hydride (80 mg, 80% dispersion in mineral oil, 2.67 mmol)was added to a cooled (−78° C.) solution of the title compound frompreparation 34 (1.0 g, 2.08 mmol) in tetrahydrofuran (10 ml), and themixture allowed to warm slowly to room temperature. 4-Fluoronitrobenzene(0.5 ml, 4.7 mmol) was added, and the reaction heated at 65° C. for 72hours. The cooled mixture was partitioned between aqueous ammoniumchloride solution and ethyl acetate, and the layers separated. Theaqueous phase was extracted with ethyl acetate, the combined organicsolutions washed with water, then brine, dried (MgSO₄) and evaporatedunder reduced pressure. The crude product was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol (100:0 to 95:5) to afford the title compound,630 mg.

[0892] δ (CDCl₃): 0.93 (6H, m), 1.52 (3H, t), 2.32 (2H, m), 2.44 (4H,m), 2.98 (6H, m), 4.72 (2H, q), 5.96 (1H, s), 6.76 (1H, s), 7.62 (2H,d), 8.32 (2H, d), 8.58 (1H, d), 8.75 (1H, d), 10.63 (1H, s).

[0893] LRMS: m/z 601 (M+1)⁺

Preparation 502-[3-Dimethylamino-n-propyl]-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethylpyrazole-5-carboxamide

[0894]

[0895] Methanesulphonyl chloride (4.95 ml, 64.0 mmol) was added to anice-cold solution of 3-dimethylamino-1-propanol (6 g, 58.2 mmol) andtriethylamine (9.7 ml, 69.8 mmol) in dichloromethane (200 ml), and thereaction stirred at room temperature for 16 hours. The mixture waspartitioned between ethyl acetate and aqueous sodium bicarbonatesolution, and the phases separated. The aqueous layer was extracted withethyl acetate, and the combined organic solutions dried (Na₂SO₄) andevaporated under reduced pressure. The residue was immediately purifiedby column chromatography on silica gel using dichloromethane:methanol(90:10) as eluant to give an oily solid, 1.5 g. This was immediatelyre-dissolved in dichloromethane (3 ml), filtered, and the filtratediluted with tetrahydrofuran (10 ml).

[0896] Sodium hydride (70 mg, 60% dispersion in mineral oil, 1.75 mmol)was added portionwise to an ice-cooled solution of the title compoundfrom preparation 34 (760 mg, 1.59 mmol) in tetrahydrofuran (15 ml), andonce addition was complete, the solution was stirred at room temperaturefor an hour.

[0897] The previously prepared solution of mesylate was then added, andthe reaction stirred at 70° C. for 16 hours. The cooled mixture waspoured into saturated sodium bicarbonate solution (120 ml), andextracted with ethyl acetate (2×100 ml). The combined organic extractswere dried (Na₂SO₄) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (89:10:1) as eluant to afford thetitle compound, 140 mg.

[0898] δ (CDCl₃): 1.02 (3H, t), 1.21 (3H, t), 1.58 (3H, t), 2.32 (6H,s), 2.40 (2H, q), 2.54 (4H, m), 2.78 (2H, t), 2.92 (2H, q), 3.08 (4H,m), 4.18 (2H, t), 4.78 (2H, q), 5.25 (1H, s), 6.66 (1H, s), 8.64 (1H,s), 8.83 (1H, s), 10.54 (1H, s).

Preparation 514-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-(piperidin-4-yl)pyrazole-5-carboxamideDitrifluoroacetate

[0899]

[0900] Trifluoroacetic acid (3 ml) was added to a solution of the titlecompound from preparation 46 (309 mg, 0.47 mmol) in dichloromethane (4ml), and the solution stirred for 2½ hours. The reaction was evaporatedunder reduced pressure and the residue triturated well with ether. Theresulting solid was sonicated in ether for 1 minute, the resultingprecipitate filtered and dried to afford the title compound as a whitesolid, 278 mg.

[0901] δ (DMSOd₆): 1.15 (6H, m), 1.46 (3H, t), 2.04 (2H, m), 2.20 (2H,m), 2.40-2.84 (6H, m), 3.00-3.22 (6H, m), 3.25-3.60 (4H, m), 3.76 (1H,m), 4.62 (4H, m), 7.27 (1H, s), 7.40 (1H, s), 8.41 (2H, m), 8.70 (2H,m), 10.24 (1H, s).

Preparation 524-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-(1-methylpiperidin-4-yl)pyrazole-5-carboxamide

[0902]

[0903] Trifluoroacetic acid (1.5 ml) was added to a solution of thetitle compound from preparation 46 (320 mg, 0.48 mmol) indichloromethane (2 ml) and the solution stirred at room temperature for2½ hours. The reaction mixture was evaporated under reduced pressure andthe residue triturated well with ether and dried under vacuum, toprovide a white solid.

[0904] Formaldehyde (217 μl, 37% aqueous, 2.90 mmol) was added to asolution of the intermediate amine in dichloromethane (8 ml), and thesolution stirred vigorously for 30 minutes. Acetic acid (88 μl, 1.69mmol) was added, the solution stirred for a further 30 minutes, thensodium triacetoxyborohydride (169 mg, 0.80 mmol) was added and thereaction stirred at room temperature for 16 hours. The reaction mixturewas poured into aqueous sodium bicarbonate solution, and extracted withethyl acetate. The combined organic extracts were dried (MgSO₄) andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(91.75:7.5:0.75) as eluant to afford the title compound, 70 mg.

[0905] δ (CDCl₃): 1.02 (3H, t), 1.22 (3H, t), 1.58 (3H, t), 1.92 (2H,m), 2.14 (2H, m), 2.25-2.45 (7H, m), 2.54 (4H, m), 2.91 (2H, q),2.99-3.16 (6H, m), 4.08 (1H, m), 4.78 (2H, q), 5.11 (1H, br s), 6.65(1H, br s), 8.63 (1H, d), 8.83 (1H, d), 10.53 (1H, s).

Preparation 534-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-(1-methylazetidin-3-yl)pyrazole-5-carboxamide

[0906]

[0907] Trifluoroacetic acid (2.5 ml) was added to a solution of thetitle compound from preparation 33 (700 mg, 1.1 mmol) in dichloromethane(3.5 ml) and the solution stirred at room temperature for 2½ hours. Thereaction mixture was evaporated under reduced pressure and the residuetriturated well with ether and dried under vacuum. The solid wassuspended in saturated aqueous sodium bicarbonate solution, extractedwith ethyl acetate, and the combined organic extracts evaporated underreduced pressure.

[0908] Formaldehyde (280 μl, 37% aqueous, 4.4 mmol) was added to asolution of the intermediate amine in dichloromethane (8 ml), and thesolution stirred vigorously for 30 minutes. Acetic acid (53 μl, 1.1mmol) was added, the solution stirred for a further 30 minutes, thensodium triacetoxyborohydride (238 mg, 1.12 mmol) was added and thereaction stirred at room temperature for 16 hours. The reaction mixturewas poured into aqueous sodium bicarbonate solution (30 ml), andextracted with ethyl acetate (2×30 ml). The combined organic extractswere dried (MgSO₄) and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (91.75:7.5:0.75) to afford thetitle compound, 470 mg.

[0909] δ (CDCl₃): 1.01 (3H, t), 1.18 (3H, t), 1.58 (3H, t), 2.40 (2H,q), 2.48 (3H, s), 2.54 (4H, m), 2.85 (2H, q), 3.10 (4H, m), 3.59 (2H,t), 3.82 (2H, t), 4.79 (2H, q), 4.96 (1H, m), 5.32 (1H, br s), 6.79 (1H,br s), 8.64 (1H, d), 8.82 (1H, d), 10.52 (1H, s).

Preparation 544-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-[2-(methylamino)ethyl]pyrazole-5-carboxamide

[0910]

[0911] A mixture of the title compound of preparation 32 (250 mg, 0.37mmol) and 10% palladium on charcoal (35 mg) in methanol (3 ml) washydrogenated at 60 psi and room temperature for 16 hours. The reactionmixture was filtered through Arbocel®, the filter pad washed withmethanol and the combined filtrates evaporated under reduced pressure.The residue was purified by column chromatography on silica gel, usingan elution gradient of dichloromethane:methanol:0.88 ammonia (90:10:0 to89:10:1) to afford the title compound (135 mg, 68%) as a white foam.

[0912] δ (CDCl₃): 1.02 (3H, t), 1.20 (3H, t), 1.60 (3H, t), 2.40 (2H,q), 2.48 (3H, s), 2.52 (4H, m), 2.94 (2H, q), 3.10 (6H, m), 4.22 (2H,t), 4.79 (2H, q), 5.28 (1H, s), 6.67 (1H, s), 8.64 (1H, s), 8.83 (1H,s), 10.54 (1H, s).

Preparation 552-[2-(Dimethylamino)ethyl]-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethylpyrazole-5-carboxamide

[0913]

[0914] Sodium hydride (88 mg, 60% dispersion in mineral oil, 2.2 mmol)was added portionwise to an ice-cold solution of the title compound frompreparation 34 (1.0 g, 2.1 mmol) in tetrahydrofuran (25 ml), and thesolution stirred for 30 minutes.

[0915] 2-Dimethylaminoethylchloride hydrochloride (451 mg, 3.15 mmol)was treated with saturated aqueous sodium bicarbonate solution, and thismixture extracted with dichloromethane (2×15 ml). The combined extractswere concentrated under reduced pressure at room temperature to a volumeof about 2 ml, and this solution diluted with tetrahydrofuran (10 ml).This was then added to the previously prepared solution, and thereaction heated under reflux for 20 hours. The cooled mixture was pouredinto aqueous saturated sodium bicarbonate solution, and extracted withethyl acetate (100 ml). The organic extract was evaporated under reducedpressure, and the residual foam was purified by column chromatography onsilica gel using ethyl acetate:diethylamine (95:5) as eluant to affordthe title compound, 300 mg.

[0916] δ (CDCl₃): 1.02 (3H, t), 1.22 (3H, t), 1.59 (9H, m), 2.40 (2H,q), 2.54 (4H, m), 2.78 (2H, t), 2.94 (2H, q), 3.09 (4H, m), 4.19 (2H,t), 4.78 (2H, q), 5.25 (1H, s), 6.65 (1H, s), 8.62 (1H, s), 8.83 (1H,s), 10.54 (1H, s).

Preparation 564-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-1-(2-methoxyethyl)pyrazole-5-carboxamide

[0917]

[0918] The title compound was obtained (70%) from the title compounds ofpreparations 25 and 14, following a similar procedure to that describedin preparation 27.

[0919] δ (CDCl₃) 1.04 (3H, t), 1.27 (3H, t), 1.59 (3H, t), 2.42 (2H, q),2.57 (4H, m), 2.72 (2H, q), 3.12 (4H, m), 3.38 (3H, s), 3.85 (2H, t),4.55 (2H, t), 4.77 (2H, q), 5.57 (1H, s), 7.92 (1H, s), 8.68 (1H, s),8.86 (1H, s), 9.82 (1H, s).

[0920] LRMS: m/z 538 (M+1)⁺

Preparation 574-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-1-(2-methoxyethyl)-3-n-propylpyrazole-5-carboxamide

[0921]

[0922] A mixture of the title compounds of preparations 26 (585 mg, 1.77mmol) and 15 (300 mg, 1.32 mmol), 1-hydroxybenzotriazole hydrate (189mg, 1.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (267 mg, 1.40 mmol) and N-ethyldiisopropylamine (0.39 ml,2.25 mmol) in dichloromethane (20 ml) was stirred at room temperaturefor 18 hours. The mixture was washed with brine (10 ml), then water (10ml) and then extracted with hydrochloric acid (1M, 3×20 ml). Thecombined acidic extracts were neutralised using sodium bicarbonatesolution, and this aqueous solution extracted with dichloromethane (3×30ml). The combined organic extracts were dried (Na₂SO₄), and evaporatedunder reduced pressure to afford the title compound as a white solid,446 mg.

[0923] δ (CDCl₃): 0.97 (3H, t), 1.67 (5H, m), 2.28 (3H, s), 2.50 (4H,m), 2.65 (2H, t), 3.10 (4H, m), 3.37 (3H, s), 3.82 (2H, t), 4.52 (2H,t), 4.76 (2H, q), 5.57 (1H, s), 7.87 (1H, s), 8.67 (1H, s), 8.85 (1H,s), 9.77 (1H, s).

[0924] LRMS: m/z 538 (M+1)⁺

Preparation 585-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0925]

[0926] Potassium bis(trimethylsilyl)amide (8.28 g, 41.6 mmol) was addedto a solution of the title compound from preparation 34 (10.0 g, 20.8mmol) and ethyl acetate (2 ml, 20 mmol) in ethanol (160 ml), and thereaction mixture heated at 120° C. for 12 hours in a sealed vessel. Thecooled mixture was evaporated under reduced pressure and the residue waspurified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant, to give thetitle compound, 3.75 g.

[0927] δ (CDCl₃): 1.03 (3H, t), 1.42 (3H, t), 1.60 (3H, t), 2.42 (2H,q), 2.58 (4H, m), 3.02 (2H, q), 3.16 (4H, m), 4.78 (2H, q), 8.66 (1H,d), 9.08 (1H, d), 11.00 (1H, s) 11.05-11.20 (1H, br s).

[0928] LRMS: m/z 462 (M+1)⁺

Preparation 595-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0929]

[0930] A mixture of the title compound from preparation 34 (500 mg, 1.04mmol), and potassium bis(trimethylsilyl)amide (436 mg, 2.19 mmol) inn-butanol (12 ml) was heated at 130° C. for 16 hours in a sealed vessel.The cooled mixture was poured into saturated aqueous sodium bicarbonatesolution, and extracted with ethyl acetate, and the combined organicextracts dried (MgSO₄) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel usingdichloromethane:methanol (96:4) as eluant to afford the title compound,128 mg.

[0931] δ (CDCl₃): 1.04 (6H, m), 1.42 (3H, t), 1.59 (2H, m), 1.96 (2H,m), 2.46 (2H, m), 2.60 (4H, m), 3.01 (2H, q), 3.19 (4H, m), 4.70 (2H,t), 8.64 (1H, d), 9.03 (1H, d), 11.09 (1H, s).

[0932] LRMS: m/z 490 (M+1)⁺

Preparation 602-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0933]

[0934] A mixture of the title compound of preparation 31 (2.02 g, 3.17mmol), and potassium bis(trimethylsilyl)amide (950 mg, 4.76 mmol) in3-methyl-3-pentanol (50 ml) was stirred under reflux for 8 hours. Thecooled mixture was concentrated under reduced pressure, the residuesuspended in ethyl acetate (100 ml), washed with water (50 ml) and brine(50 ml), dried (MgSO₄) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel, using anelution gradient of dichloromethane:methanol (100:0 to 90:10) to affordthe title compound, 124 mg.

[0935] δ (CDCl₃): −0.08 (6H, s), 0.81 (9H, s), 1.02 (3H, t), 1.40 (3H,t), 1.57 (3H, t) 2.41 (2H, q), 2.56 (4H, m), 3.14 (6H, m), 4.15 (2H, t),4.40 (2H, t), 4.74 (2H, q), 8.62 (1H, s), 9.03 (1H, s), 10.68 (1H, s).

[0936] LRMS: m/z 620 (M+1)⁺

Preparation 612-[2-[(tert-Butoxycarbonyl)(methyl)amino]ethyl]-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxypyridin-3-yl]-3-ethyl-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0937]

[0938] A mixture of the title compound from example 14 (100 mg, 0.16mmol) and potassium bis(trimethylsilyl)amide (161 mg, 0.81 mmol) inn-propanol (3 ml) was heated at 100° C. for 16 hours. The cooledreaction mixture was poured into saturated sodium bicarbonate solution(20 ml), extracted with ethyl acetate (2×30 ml), and the combinedorganic extracts evaporated under reduced pressure. The crude productwas purified by column chromatography on silica gel usingdichloromethane:methanol (97:3) as eluant to afford the title compound,71 mg.

[0939] δ (CDCl₃): 1.03 (3H, t), 1.14 (3H, t), 1.41 (3H, t), 1.45 (9H,s), 2.00 (2H, m), 2.42 (2H, q), 2.58 (7H, m), 3.01 (2H, q), 3.16 (4H,m), 3.78 (2H, t), 4.46 (2H, m), 4.63 (2H, t), 8.63 (1H, d), 9.04 (1H,d), 10.66 (1H, br s).

Preparation 625-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}-3-ethyl-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0940]

[0941] A mixture of the title compound from example 14 (123 mg, 0.20mmol), potassium bis(trimethylsilyl)amide (198 mg, 1.0 mmol) and ethylacetate (18 mg, 0.20 mmol) in n-butanol (12 ml) was heated at 110° C.for 8 hours in a sealed vessel. The cooled mixture was poured intoaqueous saturated sodium bicarbonate solution (60 ml), and extractedwith ethyl acetate (2×60 ml). The combined organic extracts were dried(MgSO₄), and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel usingdichloromethane:methanol (97:3) as eluant to give the title compound asa beige foam, 36 mg.

[0942] δ (CDCl₃): 1.02 (6H, t), 1.40 (3H, t), 1.45 (9H, s), 1.55 (2H,m), 1.95 (2H, m), 2.41 (2H, q), 2.58 (7H, m), 3.01 (2H, q), 3.16 (4H,m), 3.78 (2H, t), 4.45 (2H, m), 4.67 (2H, t), 8.63 (1H, d), 9.03 (1H,d), 10.64 (1H, s).

Preparation 632-(1-Butoxycarbonylazetidin-3-yl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0943]

[0944] A mixture of the title compound of preparation 33 (1.3 g, 2.05mmol) and potassium bis(trimethylsilyl)amide (490 mg, 2.46 mmol) inethanol (35 ml) was heated at 130° C. in a sealed vessel for 16 hours.The cooled reaction mixture was concentrated under reduced pressure, theresidue dissolved in water (15 ml), the solution neutralised usinghydrochloric acid (2N), and then saturated sodium bicarbonate added.This aqueous solution was extracted with dichloromethane (5×30 ml), thecombined organic extracts dried (MgSO₄) and evaporated under reducedpressure. The residual gum was purified by column chromatography onsilica gel, using ethyl acetate:diethylamine (96:4) as eluant to affordthe title compound, 350 mg.

[0945] δ (CDCl₃): 1.02 (3H, t), 1.38 (3H, t), 1.48 (9H, s), 1.58 (3H,t), 2.40 (2H, q), 2.57 (4H, m), 3.02 (2H, q), 3.14 (4H, m), 4.37 (2H,t), 4.42 (2H, m), 4.77 (2H, q), 5.25 (1H, m), 8.64 (1H, s), 8.81 (1H,s), 10.57 (1H, s).

Preparation 642-(1-Butoxycarbonylpiperidin-4-yl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0946]

[0947] The title compound was prepared from the title compound frompreparation 46, following a similar procedure to that described inpreparation 63. The crude product was purified by column chromatographyon silica gel using dichloromethane:methanol (95:5) as eluant to givethe title compound (62%).

[0948] δ (CDCl₃): 1.03 (3H, t), 1.38-1.60 (15H, m), 1.94 (2H, m), 2.41(4H, m), 2.57 (4H, m), 2.90 (2H, m), 3.10 (6H, m), 4.26-4.48 (3H, m),4.77 (2H, q), 8.62 (1H, d), 9.02 (1H, d), 10.60 (1H, s).

Preparation 655-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(1-tert-butoxycarbonylazetidin-3-yl)-3-ethyl-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0949]

[0950] The title compound was obtained (67%) from the title compoundfrom preparation 63 and n-butanol, following a similar procedure to thatdescribed in preparation 61.

[0951] δ (CDCl₃): 1.02 (6H, t), 1.38 (3H, t), 1.48 (9H, s), 1.57 (2H,m), 1.96 (2H, m), 2.41 (2H, q), 2.57 (4H, m), 3.02 (2H, q), 3.15 (4H,m), 4.39 (2H, m), 4.68 (4H, m), 5.26 (1H, m), 8.62 (1H, m), 9.02 (1H,m), 10.67 (1H, s).

Preparation 662-(1-tert-Butoxycarbonylazetidin-3-yl)-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-1-methylbutoxypyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0952]

[0953] A mixture of the title compound from preparation 63 (100 mg, 0.16mmol) and potassium bis(trimethylsilyl)amide (0.157 mg, 0.79 mmol) in(R)-pentan-2-ol (1 ml), and the mixture heated at 120° C. for 4 days.The cooled mixture was suspended in aqueous saturated sodium bicarbonatesolution (35 ml) and extracted with ethyl acetate (2×35 ml). Thecombined organic extracts were dried (MgSO₄) and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(95:4.7:0.3) as eluant to give the title compound, 14 mg.

[0954] δ (CDCl₃): 1.02 (6H, m), 1.38 (3H, t), 1.48 (12H, m), 1.80 (1H,m), 1.98 (1H, m), 2.42 (2H, q), 2.58 (4H, m), 3.02 (2H, q), 3.16 (4H,m), 4.40 (2H, t), 4.67 (2H, m), 5.25 (1H, m), 5.62 (1H, m), 8.62 (1H,s), 9.02 (1H, s), 10.70 (1H, s).

Preparation 675-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(1-tert-butoxycarbonylpiperidin-4-yl)-3-ethyl-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one

[0955]

[0956] The title compound was obtained (69%) from the title compoundfrom preparation 46 and n-butanol, following a similar procedure to thatdescribed in preparation 62.

[0957] δ (CDCl₃): 1.01 (6H, t), 1.34-1.60 (14H, m), 1.93 (4H, m), 2.41(4H, m), 2.57 (4H, m), 2.90 (2H, m), 3.00-3.20 (6H, m), 4.38 (3H, m),4.66 (2H, t), 8.61 (1H, d), 9.00 (1H, s), 10.58 (1H, s).

Preparation 685-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(piperidin-4-yl)-2.6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-oneDitrifluoroacetate

[0958]

[0959] A solution of the title compound from preparation 64 (48 mg,0.075 mmol) in trifluoroacetic acid (0.5 ml) and dichloromethane (0.5ml) was stirred at room temperature for 2½ hours. The mixture wasconcentrated under reduced pressure and the residue triturated well withether. The solid was then sonicated in ether for a minute, and theresulting precipitate filtered and dried to give the title compound, 54mg.

[0960] δ (DMSOd₆): 1.16 (3H, t), 1.22-1.38 (6H, m), 2.10 (2H, m), 2.38(2H, m), 3.00 (2H, q), 3.07-3.54 (14H, m), 4.50 (2H, q), 5.85 (1H, m),8.24 (1H, s), 8.44 (1H, br s), 8.74 (2H, m), 11.90 (1H, s).

Preparation 695-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-3-ethyl-2.6-dihydro-7H-pyrazolo[4.3-d]pyrimidin-7-one

[0961]

[0962] A mixture of the title compound from preparation 58 (1.0 g, 2.2mmol), and potassium bis(trimethylsilyl)amide (2.16 g, 10.8 mmol) in2-methoxyethanol (20 ml) was heated under reflux for 18 hours. Thecooled mixture was evaporated under reduced pressure and the residuepurified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (100:0 to 90:10) to give the titlecompound, 860 mg.

[0963] δ (CDCl₃): 1.03 (3H, t), 1.42 (3H, t), 2.43 (2H, q), 2.59 (4H,m), 3.02 (2H, q), 3.18 (4H, m), 3.59 (3H, s), 4.80 (2H, t), 8.63 (1H,d), 9.00 (1H, d), 11.25 (1H, brs).

[0964] LRMS: m/z 492 (M+1)⁺

Preparation 704-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-2-(2-ethoxyethyl)-3-ethylpyrazole-5-carboxamide

[0965]

[0966] 2-Bromoethyl ethyl ether (0.28 ml, 2.50 mmol) was added to amixture of the title compound from preparation 34 (1.0 g, 2.09 mmol) andcesium carbonate (816 mg, 2.50 mmol) in N,N-dimethylformamide (20 ml),and the reaction stirred at 60° C. for 12 hours. The mixture was dilutedwith water (100 ml), and extracted with ethyl acetate (2×100 ml). Thecombined organic extracts were dried (MgSO₄), evaporated under reducedpressure and the residue azeotroped with toluene. The crude product wastriturated with ether, the resulting solid filtered and dried to affordthe title compound as a crystalline solid, 550 mg.

[0967] d (DMSOd₆): 0.92 (3H, t), 1.10 (6H, m), 1.44 (3H, t), 2.30 (2H,q), 2.42 (4H, m), 2.80 (2H, q), 2.96 (4H, m), 3.40 (2H, q), 3.78 (2H,t), 4.24 (2H, t), 4.63 (2H, q), 7.29 (1H, s), 7.40 (1H, s), 8.40 (1H,d), 8.66 (1H, d), 10.40 (1H, s).

[0968] LRMS: m/z 552 (M+1)⁺

Preparation 71 Cyclopentylmethyl 4-methylbenzenesulphonate

[0969]

[0970] p-Toluenesulphonyl chloride (2.12 g, 11.1 mmol) was added to asolution of cyclopentanemethanol (1 ml, 9.25 mmol) in ether (25 ml), andthe solution cooled in an ice/salt bath. Freshly powdered potassiumhydroxide (4.7 g, 83.3 mmol) was added and the reaction mixture allowedto warm to room temperature, over 2 hours. The reaction was diluted withwater, the phases separated, and the aqueous layer extracted with ether.The combined organic solutions were dried (MgSO₄), and evaporated underreduced pressure, to give the title compound as a clear oil, 2.18 g.

[0971]¹Hnmr (CDCl₃, 400 MHz) δ: 1.20 (2H, m), 1.55 (4H, m), 1.74 (2H,m), 2.20 (1H, m), 2.43 (3H, s), 3.92 (2H, d), 7.36 (2H, d), 7.80 (2H,d).

[0972] LRMS: m/z 277 (MNa⁺)

Preparation 72 Tetrahydro-2H-pyran-4-yl Methanesulphonate

[0973]

[0974] Methanesulphonyl chloride (1.82 ml, 23.5 mmol) was added dropwiseover 10 minutes to an ice-cold solution of tetrahydro-2H-pyran-4-ol (2.0g, 19.6 mmol) and triethylamine (3.56 ml, 25.5 mmol) in dichloromethane(20 ml), and the reaction then stirred at room temperature for 72 hours.The reaction was washed with saturated aqueous sodium bicarbonatesolution (10 ml), dried (MgSO₄) and evaporated under reduced pressure togive an orange oil, that solidified on standing, 3.1 g.

[0975]¹Hnmr (CDCl₃, 400 MHz) δ: 1.88 (2H, m), 2.03 (2H, m), 3.01 (3H,s), 3.55 (2H, m), 3.95 (2H, m), 4.90 (1H, m).

[0976] LRMS: m/z 198 (MNH₄)⁺

[0977] Anal. Found: C, 39.90; H, 6.74. C₆H₁₂O₄S requires C, 39.99; H,6.71%.

Preparation 73 Methanesulphonic Acid Cyclohexylester

[0978]

[0979] The title compound was prepared according to the method describedin Tetrahedron 41; 17; 1985; 3447.

Preparation 74 (1R)-1-Methylpropyl Methanesulphonate

[0980]

[0981] A solution of methanesulphonic anhydride (8.33 g, 47.8 mmol) indichloromethane (30 ml) was added dropwise over 30 minutes to anice-cooled solution of (R)-2-butanol (4.0 ml, 43.5 mmol) andtriethylamine (6.65 ml, 47.8 mmol) in dichloromethane (70 ml). Thereaction was then allowed to warm to room temperature and stirred for 18hours. The mixture was then washed with water, 2N hydrochloric acid,then dried (Na₂SO₄) and evaporated under reduced pressure to give thetitle compound as a pale yellow oil, 7.0 g.

[0982]¹Hnmr (CDCl₃, 300 MHz) δ: 0.98 (3H, t), 1.40 (3H, d), 1.62-1.80(2H, m), 3.00 (3H, s), 4.76 (1H, m).

Preparation 75 (1S)-1-Methylpropyl Methanesulphonate

[0983]

[0984] The title compound was obtained as an oil, in 54% yield from(S)-2-butanol and methanesulphonic anhydride, following the proceduredescribed in preparation 74.

[0985]¹Hnmr (CDCl₃, 300 MHz) δ: 0.96 (3H, t), 1.38 (3H, d), 1.60-1.76(2H, m), 2.96 (3H, s), 4.70 (1H, m).

Preparation 76 (2R)-1-Methoxypropan-2-ol

[0986]

[0987] Sodium methoxide (54 g, 1.0 mol) was added portionwise toice-cooled methanol (1000 ml), and the resulting solution stirred for 20minutes in an ice-bath. (R)-Propylene oxide (58 g, 1 mol) was addeddropwise over 30 minutes, and once addition was complete, the reactionwas stirred at room temperature for 18 hours. The mixture wasconcentrated under reduced pressure, and acidified, with ice-cooling,using (1M) ethereal hydrochloric acid, and the resulting mixture stirredfor an hour, then filtered. The filtrate was dried (K₂CO₃), filtered andevaporated under reduced pressure. The residue was heated to 70° C. overdried calcium oxide for 30 minutes, then distilled at atmosphericpressure to afford the title compound as an oil, 25.4 g.

[0988] b.p. 118-120° C.

[0989]¹Hnmr (CDCl₃, 300 MHz) δ: 1.16 (3H, d), 2.28 (1H, d), 3.20 (1H,m), 3.36 (1H, m), 3.40 (3H, s), 3.97 (1H, m).

[0990] [α]_(D)−20.83° (c=1.02, dichloromethane)

Preparation 77 (1R)-2-Methoxy-1-methylethyl Methanesulphonate

[0991]

[0992] Triethylamine (8.5 ml, 61 mmol) was added to a solution of thealcohol from preparation 76 (5.0 g, 55 mmol) in dichloromethane (100ml), and the solution cooled in an ice/acetone bath. A solution ofmethanesulphonic anhydride (10.64 g, 61 mmol) in dichloromethane (50 ml)was added dropwise over 30 minutes, then the reaction stirred at roomtemperature for 18 hours. The reaction mixture was washed with water,and 2M hydrochloric acid, then dried (Na₂SO₄), and evaporated underreduced pressure to give the title compound, 2.77 g.

[0993]¹Hnmr (CDCl₃, 300 MHz) δ: 1.39 (3H, d), 3.03 (3H, s), 3.38 (3H,s), 3.44 (2H, m), 4.87 (1H, m).

Preparation 78 (1S)-2-Methoxy-1-methylethyl methanesulphonate

[0994]

[0995] S(−)-propylene oxide (17.58 g, 0.30 mol) was added dropwise over45 minutes, to a freshly prepared solution of sodium (7.0 g, 0.30 mol)in methanol (100 ml), and the mixture stirred at room temperature for 18hours. The reaction was diluted with pentane (150 ml), then acetic acid(17 ml, 0.30 mol) added slowly. The resulting mixture was filteredthrough Celite®, and the filtrate concentrated under reduced pressure.The residual oil was distilled at 30 Torr, and fractions boiling at 30°C. were collected, to give 3.3 g of an oil, containing about 30%methanol.

[0996] Triethylamine (5.56 ml, 0.04 mol) was added to a solution of thisoil in dichloromethane (60 ml), then the solution cooled in ice. Asolution of methanesulphonic anhydride (7.03 g, 0.04 mol) indichloromethane (30 ml) was added dropwise over 30 minutes, then thereaction stirred at room temperature for 18 hours. The mixture waswashed with water, and 2M hydrochloric acid, then dried (MgSO₄), andevaporated under reduced pressure to give the title compound, 3.3 g,which was used without further purification.

[0997]¹Hnmr (CDCl₃, 300 MHz) δ: 1.39 (3H, d), 3.03 (3H, s), 3.38 (3H,s), 3.44 (2H, m), 4.87 (1H, m).

Preparation 79 2-Ethoxy-5-nitro-3-pyridinecarboxylic Acid

[0998]

[0999] A suspension of 2-ethoxy-3-pyridinecarboxylic acid (16.4 g, 98mmol), and cesium carbonate (32 g, 98 mmol) in N,N-dimethylformamide(240 ml) was stirred at room temperature for 2 hours. Ethyl iodide (7.85ml, 98 mmol) was added and the reaction stirred for a further 24 hours.The reaction mixture was concentrated under reduced pressure and theresidue partitioned between aqueous sodium carbonate solution (100 ml)and ethyl acetate (100 ml). The phases were separated and the aqueouslayer extracted with ethyl acetate (2×100 ml). The combined organicsolutions were washed with brine, dried (Na₂SO₄) and evaporated underreduced pressure to afford the ethyl ester, 18.0 g, as a pale yellowoil.

[1000] Ammonium nitrate (5.36 g, 66 mmol) was added portionwise to anice-cooled solution of the oil (4.66 g, 22.3 mmol) in trifluoroaceticanhydride (50 ml) and the reaction stirred for 18 hours at roomtemperature. The reaction mixture was carefully poured into ice water(200 ml) and the resulting suspension stirred for an hour. Theprecipitate was filtered off, washed with water and dried under suctionto afford the nitro ester as a solid, 3.29 g.

[1001] Aqueous sodium hydroxide solution (4 ml, 5N, 20 mmol) was addeddropwise to a solution of the solid (5.1 g, 20 mmol) in ethanol (100 ml)and the reaction stirred at room temperature for 18 hours. The reactionmixture was concentrated under reduced pressure, the residue suspendedin water (50 ml) and acidified to pH 3 with hydrochloric acid. Thisaqueous solution was extracted with ethyl acetate (3×100 ml), thecombined organic layers washed with brine (100 ml), dried (Na₂SO₄) andevaporated under reduced pressure to give a beige solid. The crudeproduct was recrystallised from ethyl acetate/hexane to afford the titlecompound, 3.32 g, as beige crystals.

[1002]¹Hnmr (CDCl₃, 300 MHz) δ: 1.55 (3H, t), 4.78 (2H, q), 9.17 (1H,s), 9.23 (1H, s).

Preparation 804-(2-Ethoxy-5-nitropyridin-3-ylcarboxamido)-3-ethyl-2-(2-methoxyethyl)pyrazole-5-carboxamide

[1003]

[1004] A mixture of the acid from preparation 79 (4.46 g, 21.0 mmol),the pyrazole from preparation 9 (4.15 g, 19.6 mmol),1-hydroxybenzotriazole hydrate (3.51 g, 26.0 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.98 g,26.0 mmol) and N-ethyldiisopropylamine (10.38 ml, 60.0 mmol) indichloromethane (110 ml) was stirred at room temperature for 18 hours.The reaction was diluted with dichloromethane (100 ml), then washedconsecutively with water (70 ml), 10% aqueous sodium bicarbonatesolution (70 ml), and brine (70 ml), then dried (Na₂SO₄) andconcentrated under reduced pressure. The residual yellow solid waspurified by column chromatography on silica gel usingdichloromethane:methanol (95:5) as eluant. The product wasrecrystallised from ethyl acetate to afford the title compound as a paleyellow crystalline solid, 3.96 g.

[1005]¹Hnmr (CDCl₃, 400 MHz) δ: 1.21 (3H, t), 1.59 (3H, t), 2.94 (2H,q), 3.35 (3H, s), 3.80 (2H, t), 4.27 (2H, t), 4.83 (2H, q), 5.29 (1H, brs), 6.62 (1H, br s), 9.15 (1H, d), 9.32 (1H, d), 10.51 (1H, brs).

[1006] LRMS: m/z 407.5 (MH⁺)

[1007] Anal. Found: C, 50.21; H, 5.39; N, 20.66. C₁₇H₂₂N₆O₆ requires C,50.24; H, 5.46; N, 20.68%.

Preparation 814-(5-Amino-2-ethoxypyridin-3-ylcarboxamido)-3-ethyl-2-(2-methoxyethyl)pyrazole-5-carboxamide

[1008]

[1009] A mixture of the nitro compound from preparation 80 (3.86 g, 9.50mmol), and 10% palladium on charcoal (200 mg) in dichloromethane (75 ml)and ethanol (25 ml) was hydrogenated at 50 psi and room temperature for2 hours. The mixture was diluted with dichloromethane, then filteredthrough Solkafloc®, and the filtrate evaporated under reduced pressureto give the title compound, 3.63 g.

[1010]¹Hnmr (DMSOd₆, 400 MHz) δ: 1.06 (3H, t), 1.37 (3H, t), 2.75 (2H,q), 3.23 (3H, s), 3.72 (2H, t), 4.24 (2H, t), 4.39 (2H, q), 5.02 (2H, brs), 7.25 (1H, br s), 7.37 (1H, br s), 7.70 (2H, m), 10.33 (1H, s).

[1011] LRMS: m/z 377.2 (MH⁺)

Preparation 825-(5-Amino-2-ethoxypyridin-3-yl)-3-ethyl-2-(2-methoxyethyl)pyrazole-2.6-dihydro-7H-pyrazolo[4,3-d]pyrimidinone

[1012]

[1013] A mixture of the amine from preparation 81 (2.53 g, 6.72 mmol),and potassium bis(trimethylsilyl)amide (5.56 g, 27.9 mmol) in ethanol(50 ml) was heated at 120° C. in a sealed vessel for 8 hours. The cooledreaction was evaporated under reduced pressure and the residue purifiedby column chromatography on silica gel using an elution gradient ofethyl acetate:ethanol (100:0 to 96:4) to afford the title compound, 1.96g.

[1014]¹Hnmr (CDCl₃, 400 MHz) δ: 1.40 (3H, t), 1.51 (3H, t), 3.06 (2H,q), 3.30 (3H, s), 3.57 (2H, br s), 3.90 (2H, t), 4.45 (2H, t), 4.55 (2H,q), 7.77 (1H, d), 8.18 (1H, d), 11.03 (1H, br s).

[1015] LRMS: m/z 359.1 (MH⁺)

Preparation 832-Cyclobutyl-4-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethylypyrazole-5-carboxamide

[1016]

[1017] Cesium carbonate (2.7 g, 8.31 mmol) was added to a solution ofthe compound from preparation 34 (1.8 g, 3.76 mmol) inN,N-dimethylformamide (40 ml), followed by cyclobutyl bromide (388 μl,4.13 mmol), and the reaction mixture stirred at 60° C. for 3 days. Thecooled solution was partitioned between ethyl acetate and sodiumbicarbonate solution, and the layers separated. The aqueous phase wasextracted with ethyl acetate (3×), the combined organic solutions dried(MgSO₄), and evaporated under reduced pressure. The residual yellowsolid was triturated with ether to afford the title compound as a paleyellow powder, 762 mg.

[1018]¹Hnmr (CDCl₃, 400 MHz) δ: 1.00 {3H, t), 1.20 (3H, t), 1.57 (3H,t), 1.88 (2H, m), 2.40 (4H, m), 2.52 (4H, m), 2.70 (2H, m), 2.82 (2H,q), 3.08 (4H, m), 4.78 (3H, m), 5.24 (1H, br s), 6.75 (1H, br s), 8.62(1H, s), 8.81 (1H, s), 10.50 (1H, s).

Preparations 84 to 88

[1019] The compounds of the following general structure:

[1020] were prepared from the compound from preparation 34 and theappropriate alkylating agent, following a similar method to thatdescribed in preparation 83. Prep. Alkylating Yield No. R agent (%) Data84

bromide 54 ¹Hnmr(CDCl₃, 400MHz)δ: 1.02(3H, t), 1.22(3H, t), 1.58(3H, t),1.71(2H, m), 1.97(2H, m), 2.08(4H, m), 2.40(2H, q), 2.52(4H, m),2.92(2H, q), 3.10(4H, m), 4.65(1H, m), 4.78(2H, q), 5.21(1H, br s),6.66(1H, br s), 8.64(1H, d), 8.82 (1H, d), 10.50(1H, s). LRMS: m/z 548(MH⁺) 85

tosylate 52 ¹Hnmr(CDCl₃, 400MHz)δ: 1.02(3H, t), 1.15-1.38(6H, m),1.58-1.72(6H, m), 2.37-2.57(7H, m), 2.94(2H, m), 3.16 (4H, m), 4.00(2H,d), 4.78(2H, q), 5.20 (1H, br s), 6.64(1H, br s), 8.64(1H, s), 8.83(1H,s), 10.54(1H, s). LRMS: m/z 561.8(M⁺) 86¹

mesylate 25 ¹Hnmr(CDCl₃, 300MHz)δ: 1.01(3H, t), 1.21(3H, t), 1.42(2H,m), 1.58(3H, t), 1.94(6H, m), 2.40(4H, m), 2.52(4H, m), 2.88(2H, q),3.08(4H, m), 4.76(3H, m), 5.20(1H, br s), 6.66(1H, br s), 8.62 (1H, d),8.82(1H, d), 10.60(1H, s). LRMS: m/z 562.3(MH⁺) 87

mesylate 21 ¹Hnmr(CDCl₃, 300MHz)δ: 1.00(3H, t), 1.30(3H, t), 1.55(3H,t), 1.80(2H, m), 2.35(2H, m), 2.40(2H, q), 2.55(4H, m), 2.90(2H, q),3.10(4H, m), 3.50(2H, t), 4.14(2H, m), 4.30(1H, m), 4.80(2H, q),5.22(1H, br s), 6.66(1H, br s), 8.60 (1H, s), 8.80(1H, s), 10.50(1H, s).LRMS: m/z 565(MH⁺) 88

bromide 52 ¹Hnmr(CDCl₃, 300MHz)δ: 1.00(3H, t), 1.20(3H, t), 1.60(3H, t),2.18(2H, m), 2.40(2H, q), 2.50(4H, m), 2.90(2H, q), 3.08(4H, m),3.32(3H, s), 3.40(2H, t), 4.20(2H, t), 4.80(2H, q), 5.22(1H, br s),6.64(1H, br s), 8.60(1H, s), 8.80 (1H, s), 10.50(1H, br s). LRMS: m/z553(MH⁺)

Preparation 894-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-[(1R)-1-methyl-2-methoxyethyl]pyrazole-5-carboxamide

[1021]

[1022] Cesium carbonate (3.00 g, 9.20 mmol) was added to a solution ofthe compound from preparation 34 (2.0 g, 4.17 mmol) inN,N-dimethylformamide (30 ml), and the mixture stirred for 30 minutes.The mesylate from preparation 78 (0.77 g, 4.58 mmol) was added and thereaction stirred at 60° C. for 8 hours. The cooled mixture waspartitioned between ethyl acetate and water, and the pH adjusted to 8,using solid carbon dioxide. The layers were separated, and the aqueousphase extracted with ethyl acetate (2×). The combined organic extractswere dried (Na₂SO₄), and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel using anelution gradient of methanol:dichloromethane (1:99 to 8:92) to affordthe title compound, 300 mg.

[1023]¹Hnmr (CDCl₃, 300 MHz) δ: 1.02 (3H, t), 1.23 (3H, t), 1.48 (3H,d), 1.58 (3H, t), 2.40 (2H, q), 2.52 (4H, m), 2.90 (2H, m), 3.08 (4H,m), 3.30 (3H, s), 3.60 (1H, m), 3.78 (1H, m), 4.56 (1H, m), 4.78 (2H,q), 5.30 (1H, br s), 6.66 (1H, br s), 8.63 (1H, d), 8.82 (1H, d), 10.48(1H, s).

[1024] LRMS: m/z 552.3 (MH⁺)

Preparation 904-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-ylcarboxamido]-3-ethyl-2-[(1S)-1-methyl-2-methoxyethyl)pyrazole-5-carboxamide

[1025]

[1026] The title compound was obtained as an oil in 52% yield, from thecompound from preparation 34 and the mesylate from preparation 77,following the procedure described in preparation 89.

[1027]¹Hnmr (CDCl₃, 300 MHz) δ: 1.01 (3H, t), 1.22 (3H, t), 1.48 (3H,d), 1.58 (3H, t), 2.40 (2H, q), 2.54 (4H, m), 2.90 (2H, m), 3.08 (4H,m), 3.30 (3H, s), 3.61 (1H, m), 3.78 (1H, m), 4.56 (1H, m), 4.78 (2H,q), 5.25 (1H, br s), 6.66 (1H, br s), 8.63 (1H, d), 8.82 (1H, d), 10.48(1H, s).

[1028] LRMS: m/z 552.4 (MH⁺)

Preparations 91 to 94

[1029] The compounds of the following general structure:

[1030] were prepared from the compound from preparation 35 and theappropriate alkylating agent, following a similar method to thatdescribed in preparation 83. Prep. Alkylating Yield No. R agent (%) Data91¹

bromide 34 ¹Hnmr(CDCl₃, 400MHz)δ: 0.95 (3H, t), 1.20(3H, t), 1.40(2H,m), 1.0(3H, t), 1.86(2H, m), 2.25(3H, s), 2.46(4H, m), 2.88(2H, q), 3.09(4H, m), 4.05(2H, t), 4.75(2H, t), 5.25(1H, br s), 6.65(1H, br s), 8.65(1H, s), 8.85(1H, s), 10.55(1H, s). 92

bromide 47 ¹Hnmr(CDCl₃, 400MHz)δ: 0.41 (2H, m), 0.62(2H, m), 1.22(4H,m), 1.59(3H, t), 2.26(3H, s), 2.48(4H, m), 2.98(2H, q), 3.10(4H, m),3.98 (2H, d), 4.78(2H, q), 5.27(1H, br s), 6.68(1H, br s), 8.65(1H, d),8.85 (1H, d), 10.57(1H, s). 93

mesylate 45 ¹Hnmr(CDCl₃, 400MHz)δ: 0.82 (3H, t), 1.22(3H, t), 1.60(6H,m), 1.80(1H, m), 2.00(1H, m), 2.23(3H, s), 2.50(4H, m), 2.85(2H, m),3.10 (4H, m), 4.22(1H, m), 4.80(2H, q), 5.20(1H, br s), 6.70(1H, br s),8.60 (1H, s), 8.82(1H, s), 10.50(1H, s). LRMS: m/z 522.0(MH⁺) 94

mesylate 42 ¹Hnmr(CDCl₃, 400MHz)δ: 0.82 (3H, t), 1.22(3H, t), 1.60(6H,m), 1.80(1H, m), 2.00(1H, m), 2.23(3H, s), 2.50(4H, m), 2.85(2H, m),3.10 (4H, m), 4.22(1H, m), 4.80(2H, q), 5.20(1H, br s), 6.70(1H, br s),8.60 (1H, s), 8.82(1H, s), 10.50(1H, s). LRMS: m/z 522.0(MH⁺)

Preparation 95 2-Ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic Acid

[1031] (a) 2-Hydroxy-5-sulfonicotinic Acid

[1032] 2-Hydroxynicotinic acid (27 Kg, 194.2 mol) was added portionwiseto 30% oleum (58.1 Kg) at 50° C. over 1 hr. This caused an exotherm to82° C. The reaction mixture was heated further to 140° C. Aftermaintaining this temperature for 12 hrs the reactor contents were cooledto 15C and filtered. The filter cake was then re-slurried with acetone(33 Kg) at room temperature, filtered and dried to afford the titlecompound (35.3 Kg, 83%) as a white solid. Decomposition pt 273° C. δ(DMSO_(d6)): 7.93 (1H, d), 8.42 (1H, d). m/z (Found:220 [M+H]⁺, 100%.C₆H₆NO₆S requires 220.17).

[1033] (b) Ethyl 2-hydroxy-5-sulfonicotinoate

[1034] 2-Hydroxy-5-sulfonicotinic acid (500 g, 2.28 mol) was dissolvedin ethanol (2.5 L) with stirring and heated to 80° C. After 30 mins 0.5L of solvent was distilled off, then replaced with fresh ethanol (0.5 L)and taken back to 80° C. After a further 60 mins 1.0 L of solvent wasdistilled off, then replaced with fresh ethanol (1.0 L) and taken backto 80° C. After a further 60 mins 1.0 L of solvent was distilled off,the reaction cooled to 22° C. and stirred for 16 hr. The precipitatedproduct was filtered, washed with ethanol (0.5 L) and dried at 50° C.under vacuum to afford the title compound (416 g, 74%) as a white solid.Decomposition pt 237° C. δ (DMSOd₆): 1.25 (3H, t), 4.19 (2H,q), 7.66(1H, d), 8.13 (1H, d). m/z (Found:248 [M+H]⁺, 100%. C₈H₁₀NO₆S requires248.22).

[1035] (c) Ethyl 2-chloro-5-chlorosulfonicotinoate

[1036] Ethyl 2-hydroxy-5-sulfonicotioate (24.7 g, 0.1 mol) was slurriedin thionyl chloride (238 g, 2.0 mol) and dimethylformamide (1.0 mL) withstirring. The reaction mixture was then heated to reflux for 2.5 hr. Thebulk of the thionyl chloride was removed under vacuum with residualthionyl chloride removed with a toluene azeotrope to afford the crudetitle compound (30.7 g, 108%) as a yellow oil. d (CDCl₃): 1.46 (3H, t),4.50 (2H, q), 8.72 (1H, d), 9.09 (1H, d). This was taken directly ontothe next step.

[1037] (d) Ethyl 2-chloro-5-(4-ethyl-1-piperazinylsulfonyl)nicotinoate

[1038] Crude ethyl 2-chloro-5-chlorosulfonicotinoate (30.7 g, 0.1 molassumed) was dissolved in ethyl acetate (150 mL) with stirring then icecooled. To this was added a solution of N-ethylpiperazine (11.4 g, 0.1mol) and triethylamine (22.5 g, 0.22 mol) in ethyl acetate (50 mL),carefully over 30 mins, keeping the internal temperature below 10° C.Once the addition was complete the reaction was allowed to warm to 22°C. and stir for 1 hr. The solid was filtered off and the remainingfiltrate was concentrated under vacuum to afford the crude titlecompound (37.1 g, 103%) as a crude yellow gum. δ (CDCl₃): 1.10 (3H, t),1.42 (3H, m), 2.50 (2H, m), 2.60 (4H, m), 3.19 (4H, m), 4.43 (2H, q),8.40 (1H, d), 8.80 (1H, d). m/z (Found:362 [M+H]⁺, 100%. C₁₄H₂₁ClN₃O₄Srequires 362.85).

[1039] (e)Ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinoate

[1040] A solution of Ethyl2-chloro-5-(4-ethyl-1-piperazinylsulfonyl)nicotinoate (36.1 g, 0.1 mol)in ethanol (180 mL) was cooled to 10° C. with stirring. Sodium ethoxide(10.2 g, 0.15 mol) was added portionwise keeping the temperature below20° C. The reaction mixture was then stirred at ambient temperature for18 hours. The precipitate was filtered off and water (180 mL) added tothe filtrate. The filtrate was then heated to 40° C. for 1 hour. Ethanol(180 mL) was then distilled off at ambient pressure and the remainingaqueous solution allowed to cool to ambient temperature. Theprecipitated product was then filtered off, washed with water and driedunder vacuo at 50° C. to afford the title compound (12.6 g, 34%) as alight brown solid. M.p. 66-68° C. δ (CDCl₃): 1.04 (3H, t), 1.39 (3H, t),1.45 (3H, t), 2.41 (2H, q), 2.52 (4H, m), 3.08 (4H, m), 4.38 (2H, q),2.57 (2H, q), 8.38 (1H, d), 8.61 (1H, d). m/z (Found:372 [M+H]⁺, 100%.C₁₆H₂₆N₃O₅S requires 372.46).

[1041] (f) 2-Ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic Acid

[1042] Ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinoate (10.2g, 0.0275 mol) was dissolved in toluene (50 mL) and a solution of sodiumhydroxide (1.1 g, 0.0275 mol) in water (20 mL) added to it. This twophase mixture was then stirred vigorously at ambient temperatureovernight. The aqueous phase was separated off and adjusted to pH=5.6 byaddition of c. hydrochloric acid. The precipitated product was slurriedwith ice cooling for 15 minutes, filtered, water washed and dried undervacuo at 50° C. to afford the title compound as an off-white solid. Mpt206-207° C. δ (CDCl₃): 1.25 (3H, t), 1.39 (3H, t), 2.82 (2H, q), 3.03(4H, m), 3.25 (4H, m), 4.50 (2H, q), 8.25 (1H, d), 8.56 (1H, d). m/z(Found:344 [M+H]⁺, 100%. C₁₄H₂₂N₃O₅S requires 344.38).

[1043] This step 95(f) is already set out in preparation 23 ofPCT/IB99/00519 (herein incorporated by reference) and the yield obtainedis 88%.

Preparation 96N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide

[1044] (a) Ethyl 3-ethyl-1H-pyrazole-5-carboxylate

[1045] To a stirred solution of 2,2-dimethoxybutane (10 g, 84.7 mMol) inCH₂Cl₂ (50 mL) under a nitrogen atmosphere at 0° C. was added pyridine(13.7 mL, 169.5 mMol). The reaction mixture was maintained at 0° C. anda solution of trichloroacetyl chloride (18.9 mL, 169.5 mMol) in CH₂CL₂(35 mL) was added over 1 hour with constant stirring. The yellow-orangesolution begins to precipitate a white solid as the reaction progresses.The reaction mixture is allowed to warm to room temperature over 20 h.The reaction mixture was diluted with ethanol (150 mL) and re-cooled to0° C. before treatment with hydrazine hydrate (8.2 mL, 169.5 mMol) as asolution in ethanol (35 mL) over 30 min. The reaction was heated to 50°C. and solvent was distilled at atmospheric pressure. The temperaturewas increased until the head temperature reached 78° C. Reflux wasmaintained for a further 2 h, before cooling to room temperature. Thereaction mixture was diluted with water (250 mL) and ethanol was removedby evaporation at reduced pressure. The resultant mixture was extractedwith CH₂Cl₂ (3×200 mL). The combined organics were dried (MgSO₄),filtered and evaporated at reduced pressure to afford the title compoundas a brown oil, 12.05 g, 85%.

[1046]¹H NMR (300 MHz, CDCl₃): δ=1.20 (3H, t), 1.28 (3H, t), 2.67 (2H,q), 4.29 (2H, q), 6.55 (1H, s), 12.56 (1H, s).

[1047] LRMS m/z=167.1 [M−H]⁺, C₈H₁₂N₂O₂ requires 168.2.

[1048] (b) Ethyl 3-ethyl-1H-pyrazole-5-carboxylic Acid

[1049] Aqueous sodium hydroxide solution (10M; 100 ml, 1.0 mol) wasadded dropwise to a stirred suspension of the title compound ofPreparation 96(a) (66.0 g, 0.39 mol) in methanol and the resultingsolution heated under reflux for 4 hours. The cool reaction mixture wasconcentrated under reduced pressure to ca. 200 ml, diluted with water(200 ml) and this mixture washed with toluene (3×100 ml). The resultingaqueous phase was acidified with concentrated hydrochloric acid to pH 4and the white precipitate collected and dried by suction to provide thetitle compound (34.1 g). δ (DMSO_(d6)): 1.13 (3H,t), 2.56 (2H,q), 6.42(1H,s).

[1050] (c) 4-Nitro-3-n-propyl-1H-pyrazole-5-carboxylic Acid

[1051] Fuming sulphuric acid (17.8 ml) was added dropwise to stirred,ice-cooled fuming nitric acid (16.0 ml), the resulting solution heatedto 50° C., then 3-n-propyl-1H-pyrazole-5-carboxylic acid (Chem. Pharm.Bull., 1984, 32, 1568; 16.4 g, 0.106 mol) added portionwise over 30minutes whilst maintaining the reaction temperature below 60° C. Theresulting solution was heated for 18 hours at 60° C., allowed to cool,then poured onto ice. The white precipitate was collected, washed withwater and dried by suction to yield the title compound (15.4 g), m.p.170-172° C. Found: C, 42.35; H, 4.56; N, 21.07. C₇H₉N₃O₄ requires C,42.21; H, 4.55; N, 21.10%. δ (DMSOd₆): 0.90 (3H,t), 1.64 (2H,m), 2.83(2H,m), 14.00 (1H,s).

[1052] (d) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic Acid

[1053] Obtained from the title compound of Preparation 96(b), by analogywith the process of Preparation 96(c), as a brown solid (64%). δ(DMSO_(d6)): 1.18 (3H,t), 2.84 (2H,m), 13.72 (1H,s).

[1054] (e) 4-Nitro-3-n-propyl-1H-pyrazole-5-carboxamide

[1055] A solution of the title compound of Preparation 96(c) (15.4 g,0.077 mol) in thionyl chloride (75 ml) was heated under reflux for 3hours and then the cool reaction mixture evaporated under reducedpressure. The residue was azeotroped with tetrahydrofuran (2×50 ml) andsubsequently suspended in tetrahydrofuran (50 ml), then the stirredsuspension ice-cooled and treated with gaseous ammonia for 1 hour. Water(50 ml) was added and the resulting mixture evaporated under reducedpressure to give a solid which, after trituration with water and dryingby suction, furnished the title compound (14.3 g), m.p. 197-199° C.Found: C, 42.35; H, 5.07; N, 28.38. C₇H₁₀N₄O₃ requires C, 42.42; H,5.09; N, 28.27%. δ (DMSOd₆): 0.90 (3H,t), 1.68 (2H,m), 2.86 (2H,t), 7.68(1H,s), 8.00 (1H,s).

[1056] (f) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide

[1057] Obtained from the title compound of Preparation 96(d), by analogywith Preparation 96(e), as a white solid (90%). 6 (DMSOd₆): 1.1.7(3H,t), 2.87 (2H,m), 7.40 (1H,s), 7.60 (1H,s), 7.90 (1H,s). LRMS: m/z185 (M+1)⁺.

[1058] (g)(i)5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide.

[1059] A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (2.5 kg,13.6 Mol), sodium carbonate (1.8 Kg, 17.0 Mol) and 2-bromoethyl methylether (1.98 kg, 14.2 Mol) in THF (22.5 L) and water (2.5 L) was heatedunder reflux and stirred for 20 hours. The mixture was cooled to ambienttemperature and CH₂Cl₂ (67.5 L) and water (22.5 L) were added. Theresultant organic and aqueous layers were separated. The aqueous phasewas extracted with CH₂Cl₂ (22.5 L) and the combined organic solution wasdistilled under atmospheric pressure and replaced with ethyl acetate (33L) to a final volume of 17 L. The cooled mixture was granulated atambient temperature for 2 hours, filtered and washed with ethyl acetate(2.5 L). This afforded5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a whitecrystalline solid, 2.10 kg, 57%. m.p.=140° C. Found: C, 44.46; H, 5.79;N, 23.01. C₉H₁₄N₄O₄ requires C, 44.63; H, 5.79; N, 23.14%.

[1060] δ (CDCl₃): 1.18 (3H, t), 2.98 (2H, q), 3.22 (3H, s), 3.77 (2H,t), 4.28 (2H, q), 6.03 (1H, s), 7.36 (1H, s).

[1061] LRMS: m/z=243 (M+1)⁺

[1062] (g)(ii)5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide.

[1063] A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (25 g,0.136 Mol), sodium carbonate (18 g, 0.17 Mol) and sodium iodide (20.4 g,0.136 Mol) were suspended in ethyl methyl ketone (125 mL) at roomtemperature. 2-bromoethyl methyl ether (12.8 mL, 0.142 Mol) was addedand the mixture was heated to reflux and stirred for 70 hours. Themixture was cooled to ambient temperature and water (250 mL) was added.The resultant slurry was warmed to reflux and held at that temperaturefor 30 min before cooling to room temperature. The resultant precipitatewas granulated at room temperature for 3 h, filtered and vacuum dried toafford 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as ayellow crystalline solid 24.3 g, 74%. Data as reported for Example(b)(i).

[1064] (h) 4-Amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide.

[1065] A mixture of5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide (20 g, 82.6mMol) and 5% Pd/C (1 g) in methanol (200 mL) was pressurised at 50psi/25° C. in a sealed vessel and stirred for 15 hours. At the end ofthe reaction the mixture was filtered through arbocel and the filtercake was washed with methanol. The methanolic solution was distilled atatmospheric pressure and replaced with ethyl acetate to a final volumeof 100 mL. The cooled mixture was granulated at ambient temperature for2 h filtered and washed with ethyl acetate (20 mL) to afford4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide as a whitecrystalline solid, 15 g, 88%. m.p.=131° C. Found: C, 50.75; H, 7.62; N,26.38. C₉H₁₆N₄O₂ requires C, 50.94; H, 7.55; N, 26.42%.

[1066] δ (CDCl₃): 1.20 (3H, t), 2.63 (2H, q), 3.32 (3H, s), 3.74 (2H,t), 3.95 (2H, s), 4.15 (2H, t), 5.27 (1H, s), 6.59 (1H, s).

[1067] LRMS: m/z=213 (M+1)⁺

[1068] (i)N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide.

[1069] 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (2.31kg, 6.73 Mol) was suspended in ethyl acetate (16.2 L) and1,1-carbonyldimidazole (1.09 kg, 6.73 Mol) was added at roomtemperature. The reaction mixture was heated at 45° C. for 40 minutesand then the reaction was stirred for a further 40 minutes at reflux.After cooling to ambient temperature4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (1.5 kg,7.06 Mol) was added to the cooled mixture, and the reaction stirred fora further 15 hours under reflux. The mixture was cooled filtered and thefilter cake was washed with 90% water/10% ethyl acetate, (2 mL/g) toaffordN-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl) nicotinamide as an off white crystalline solid, 3.16 kg, 88%.m.p.=156° C. Found: C, 51.33; H, 6.56; N, 18.36. C₂₃H₃₅N₇O₆S requires C,51.40; H, 6.53; N, 18.25%.

[1070] δ (CDCl₃): 1.04 (3H, t), 1.22 (3H, t), 1.60 (3H, t), 2.44 (2H,q), 2.54 (4H, m), 2.96 (2H, q), 3.12 (4H, m), 3.36 (3H, s), 3.81 (2H,t), 4.27 (2H, t), 4.80 (2H, q), 5.35 (1H, s), 6.68 (1H, s), 8.66 (1H,d), 8.86 (1H, d), 10.51 (1H, s).

[1071] LRMS: m/z=539 (M+1)⁺

[1072] Additionally, in accordance with the invention, the intermediatecompounds (XIV) and (XB) (as illustrated in Schemes 2 and 3) can beprepared from commercially available starting materials (2-hydroxynicotinic acid) in better yield than the corresponding reaction sequencein PCT/IB99/00519. For example, compound (XIV) (wherein Q and W are OEt)is formed in a yield of 14.5% in preparation 18 of PCT/IB99/00519 (i.e.from a reaction sequence of prepation 1,3,5,7 and 18) whereas the samecompound is prepared in a yield of 23% in accordance with the presentinvention (see Preparation 95). More preferably the whole or part of thereaction sequence for the formation of compounds (XIV) and (XB) can betelescoped together in accordance with the invention to provide an evenbetter yield. Thus compound (XB) (wherein X is OEt) is prepared in ayield of 35% (see Preparation 95 herein). Furthermore, the reactionscheme of the present invention is safer and cheaper to operate, and inthe case of the telescoped process also involves less steps (andprocessing time).

[1073] It will be appreciated that formation of compounds of formula(XB) and (XIV) from (XV) respectively is an independent invention and ispreferably prepared from 2-hydroxynicotinic acid as outlined herein.Likewise each and every step (and telescoped step) in Schemes 2 and 3are independent inventions, although in a preferred aspect compounds offormula (I), (IA) and (IB) are prepared from nicotinic acid inaccordance with Schemes 2 and 3.

[1074] Thus in a further aspect of the invention a compound of formula(XVII) is formed by reacting 2-hydroxynicotinic acid or a salt thereofin the presence of SO₃ in a solvent.

1. A compound of the formula (I):

or a pharmaceutically or veterinarily acceptable salt, or apharmaceutically or veterinarily acceptable solvate or pro-drug thereof,wherein R¹ is C₁ to C₆ alkyl or C₃ to C₆ alkenyl, C₃ to C₆ cycloalkyl orC₄ to C₆ cycloalkenyl wherein said alkyl group may be branched orstraight chain and wherein when R¹ is C₁ to C₃ alkyl said alkyl group issubstituted by; and wherein when R¹ is C₄ to C₆ alkyl, C₃ to C₆ alkenylor C₃ to C₆ cycloalkyl said alkyl, alkenyl or cycloalkyl group isoptionally substituted by; one or more substituents selected from:hydroxy; C₁ to C₄ alkoxy; C₃ to C₆ cycloalkyl; phenyl substituted withone or more substitutents selected from C₁ to C₃ alkyl, C₁ to C₄ alkoxy,C₁ to C₄ haloalkyl, C₁ to C₄ haloalkoxy, halo, CN, NO₂, NHR¹, NHCOR¹²NHSO₂R¹², SO₂R¹², SO₂NHR¹¹, COR¹¹ or CO₂R¹¹ wherein said haloalkyl andhaloalkoxy groups contain one or more halo atoms; NR⁷R⁸, CONR⁷R⁸ orNR⁷COR¹¹ wherein R⁷ and R8 are each independently selected from H, C₁ toC₄ alkyl, C₃ to C₄ alkenyl, CO₂R⁹ or SO₂R⁹ and wherein said alkyl oralkenyl groups are optionally substituted by C₁ to C₄ haloalkyl or C₁ toC₄ haloalkoxy; Het¹; Het² or Het³; or R¹ is Het⁴ or phenyl wherein saidphenyl group is optionally substituted by one or more substituentsselected from C₁ to C₄ alkyl, C₃ to C₄ alkenyl, C₁ to C₄ alkoxy, halo,CN, CF₃, OCF₃, NO₂, NHR¹¹ NHCOR¹², NHSO₂R¹², SO₂R¹², SO₂NHR¹¹, COR¹¹,CO₂R¹¹; R² is C₁ to C₆ alkyl, C₃ to C₆ alkenyl or (CH₂)_(n)(C₃ to C₆cycloalkyl) wherein n is 0, 1 or 2; R¹³ is OR³ or NR₅R⁶; R³ is C₁ to C₆alkyl optionally substituted with one or two substituents selected fromC₃ to C₅ cycloalkyl, hydroxy, C₁ to C₄ alkoxy, benzyloxy, NR⁵R⁶, phenyl,Het¹, He, Het³ or Het⁴ wherein the C₁ to C₆ alkyl and C₁ to C₄ alkoxygroups may optionally be terminated by a haloalkyl group such as CF₃ andwherein the C₃-C₅ cycloalkyl group may optionally be substituted byC₁-C₄ alkyl, hydroxy or halo; C₃ to C₆ cycloalkyl; Het¹, Het², Het³ orHet⁴; R⁴ is a piperazin-1-ylsulphonyl group having a substituent R¹⁰ atthe 4-position of the piperazinyl group wherein said piperazinyl groupis optionally substituted with one or two C₁ to C₄ alkyl groups and isoptionally in the form of its 4-N-oxide; R⁵ and R⁶ are eachindependently selected from H and C₁ to C₄ alkyl optionally substitutedwith C₃ to C₅ cycloalkyl or C₁ to C₄ alkoxy, or, together with thenitrogen atom to which they are attached, form an azetidinyl,pyrrolidinyl, piperidinyl or morpholinyl group; R⁷ and R⁸ are eachindependently selected from H, C₁ to C₄ alkyl, C₃ to C₄ alkenyl, CO₂R⁹or SO₂R⁹; R⁹ is C₁ to C₄ alkyl optionally substituted with C₁ to C₄haloalkyl, C₁ to C₄ haloalkoxy or phenyl wherein said phenyl group isoptionally substituted by one or more substituents selected from C₁ toC₄ alkyl optionally substituted by C₁ to C₄ haloalkyl or C₁ to C₄haloalkoxy, C₁ to C₄ alkoxy, halo, CN, NO₂, NHR¹¹, NHCOR¹², NHSO₂R¹²,SO₂R¹², SO₂NHR¹¹, COR¹ or CO₂R¹¹; R¹⁰ is H; C₁ to C₄ alkyl optionallysubstituted with one or two substituents selected from hydroxy, NR⁵R⁶,CONR⁵R⁶, phenyl optionally substituted with C₁ to C₄ alkyl or C₁ to C₄alkoxy; C₃ to C₆ alkenyl or Het⁴; R¹¹ is H, C₁ to C₄ alkyl, C₃ to C₄alkenyl, CO(C₁ to C₄ alkyl) or C₁ to C₄ haloalkyl; R¹² is C₁ to C₄alkyl, C₃ to C₄ alkenyl, C₁ to C₄ haloalkyl or C₁ to C₄ haloalkoxy; Het¹is an N-linked 4-, 5- or 6-membered nitrogen-containing heterocyclicgroup optionally containing one or more further heteroatoms selectedfrom S, N or O; Het² is a C-linked 5-membered heterocyclic groupcontaining an O, S or N heteroatom optionally containing one or moreheteroatoms selected from N, O or S; Het³ is a C-linked 6-memberedheterocyclic group containing an O or S heteroatom optionally containingone or more heteroatoms selected from O, S or N or Het³ is a C-linked6-membered heterocyclic group containing three N heteroatoms; Het⁴ is aC-linked 4-, 5- or 6-membered heterocyclic group containing one, two orthree heteroatoms selected from S, O or N; and wherein any of saidheterocyclic groups Het¹, Het², Het³ or Het⁴ may be saturated, partiallyunsaturated or aromatic and wherein any of said heterocyclic groups maybe optionally substituted with one or more substituents selected from C₁to C₄ alkyl, C₃ to C₄ alkenyl, C₁ to C₄ alkoxy, halo, CF₃, CO₂R¹¹,COR¹¹, SO₂R¹², NHR¹¹ or NHCOR¹² and/or wherein any of said heterocyclicgroups is benzo-fused; with the provisos that (a) when R¹ is C₁ to C₃alkyl then Het¹ is not morpholinyl or piperidinyl and (b) when R¹ is C₁to C₃ alkyl substituted by phenyl then said phenyl group is notsubstituted by C₁ to C₄ alkoxy, CN, halo, CF₃, OCF₃ or C₁ to C₄ alkyl.2. A compound according to claim 1 wherein R¹ is C₁ to C₆ alkyl or C₃ toC₆ alkenyl wherein said alkyl or alkenyl groups may be branched chain orstraight chain or R¹ is C₃ to C₆ cycloalkyl or C₄ to C₆ cycloalkenyl andwherein when R¹ is C₁ to C₃ alkyl said alkyl group is substituted by;and wherein when R¹ is C₄ to C₆ alkyl, C₃ to C₆ alkenyl, C₃ to C₆cycloalkyl or C₄ to C₆ cycloalkenyl said alkyl, alkenyl, cycloalkyl orcycloalkenyl group is optionally substituted by; one or moresubstituents selected from: hydroxy; C₁ to C₄ alkoxy; C₃ to C₄cycloalkyl; phenyl substituted with one or more substitutents selectedfrom C₁ to C₃ alkyl, C₁ to C₄ alkoxy, C₁ to C₄ haloalkyl or C₁ to C₄haloalkoxy, halo, CN, NO₂, NHR¹¹, NHCOR¹², NHSO₂R¹², SO₂R¹², SO₂NHR¹¹,COR¹¹, CO₂R¹¹ wherein said haloalkyl and haloalkoxy groups contain oneor more halo atoms; NR⁷R⁸, CONR⁷R⁸ or NR⁷COR¹¹; a Het¹ group which is anN-linked 4-membered N-containing heterocyclic group; a Het² group whichis a C-linked 5-membered heterocyclic group containing an O, S or Nheteroatom optionally containing one or more heteroatoms selected fromN, O or S; a Het³ group which is a C-linked 6-membered heterocyclicgroup containing an O or S heteroatom optionally containing one or moreheteroatoms selected from O, S or N or a Het³ group which is a C-linked6-membered heterocyclic group containing three N heteroatoms; whereinR⁷, R⁸, R¹¹ and R¹² are as previously defined herein or R¹ is a Het⁴group which is a C-linked 4- or 5-membered heterocyclic group containingone heteroatom selected from S, O or N; a Het⁴ group which is a C-linked6-membered heterocyclic group containing one, two or three heteroatomsselected from S or O; a Het⁴ group which is a C-linked 6-memberedheterocyclic group containing three nitrogen heteroatoms; a Het⁴ groupwhich is a C-linked 6-membered heterocyclic group containing one or twonitrogen heteroatoms which is substituted by one or more substitutentsselected from C₁ to C₄ alkyl, C₁ to C₄ alkoxy, CO₂R¹¹, SO₂R², COR¹¹,NHR¹¹ or NHCOR¹² and optionally including a further heteroatom selectedfrom S, O or N wherein any of said heterocyclic groups Het¹, Het², Het³or Het⁴ is saturated, partially unsaturated or aromatic as appropriateand wherein any of said heterocyclic groups is optionally substitutedwith one or more substituents selected from C₁ to C₄ alkyl, C₃ to C₄alkenyl, C₁ to C₄ alkoxy, halo, CO₂R¹¹, SO₂R², COR¹¹ or NHR¹¹ whereinR¹¹ is as defined hereinbefore and/or wherein any of said heterocyclicgroups is benzo-fused; or R¹ is phenyl substituted by one or moresubstituents selected from CF₃, OCF₃, SO₂R¹² or CO₂R¹² wherein R¹² is C₁to C₄ alkyl which is optionally substituted by phenyl, C₁ to C₄haloalkyl or C₁ to C₄ haloalkoxy wherein said haloalkyl and haloalkoxygroups contain one or more halo atoms; R² is Cto C₆ alkyl; R¹³ is OR³;R³ is C₁ to C₆ alkyl optionally substituted with one or two substituentsselected from C₃ to C₅ cycloalkyl, hydroxy, C₁ to C₄ alkoxy, benzyloxy,NR⁵R⁶, phenyl, furanyl, tetrahydrofuranyl or pyridinyl wherein said C₁to C₆ alkyl and C₁ to C₄ alkoxy groups may optionally be terminated by ahaloalkyl group such as CF₃; or R³ is C₃ to C₆ cycloalkyl, 1-(C₁ to C₄alkyl)piperidinyl, tetrahydrofuranyl or tetrahydropyranyl; R⁴ is apiperazin-1-ylsulphonyl group having a substituent R¹⁰ at the 4-positionof the piperazinyl group wherein said piperazinyl group is optionallysubstituted with one or two C₁ to C₄ alkyl groups and is optionally inthe form of its 4-N-oxide; R⁵ and R⁶ are each independently selectedfrom H and C₁ to C₄ alkyl optionally substituted with C₃ to C₅cycloalkyl or C₁ to C₄ alkoxy, or, together with the nitrogen atom towhich they are attached, form an azetidinyl, pyrrolidinyl, piperidinylor morpholinyl group; and R¹⁰ is H; C₁ to C₄ alkyl optionallysubstituted with one or two substituents selected from hydroxy, NR⁵R⁶,CONR⁵R⁶, phenyl optionally substituted with C₁ to C₄ alkyl or C₁ to C₄alkoxy; C₃ to C₆ alkenyl; Het⁴; with the proviso that when R¹ is C₁ toC₃ alkyl substituted by phenyl then said phenyl group is not substitutedby C₁ to C₄ alkoxy; CN; CF₃; halo; OCF₃; or C₁ to C₄ alkyl.
 3. Acompound according to claim 2 wherein R¹ is C₁ to C₆ alkyl wherein saidalkyl may be branched or straight chain or R¹ is C₃ to C₆ cycloalkyl andwherein when R¹ is C₁ to C₃ alkyl said alkyl group is substituted by;and wherein when R¹ is C₄ to C₆ alkyl or C₃ to C₆ cycloalkyl said alkylor cycloalkyl group is optionally substituted by; one or moresubstituents selected from: hydroxy; C₁ to C₂ alkoxy; C₃ to C₅cycloalkyl; NR⁷R⁸, NR⁷COR¹¹ or COR¹¹ wherein R⁷ and R⁸ are eachindependently selected from H, C₁ to C₄ alkyl or CO₂R⁹ wherein R⁹ andR¹¹ are as previously defined herein; a Het¹ group which is an N-linked4-membered N-containing heterocyclic group; a Het³ group which is aC-linked 6-membered heterocyclic group containing an O or S heteroatomoptionally containing one or more heteroatoms selected from O, S or N ora Het³ group which is a C-linked 6-membered heterocyclic groupcontaining three N heteroatoms; or R¹ is a Het⁴ group which is aC-linked 4-membered heterocyclic group containing one heteroatomselected from S, O or N or R¹ is a Het⁴ group which is a C-linked6-membered heterocyclic group containing one, two or three heteroatomsselected from S or O wherein any of said heterocyclic groups Het¹, Het²,Het³ or Het⁴ is saturated, partially unsaturated or aromatic and isoptionally substituted with one or more substituents selected from C₁ toC₄ alkyl, C₁ to C₄ alkoxy, —CO₂R¹¹, —SO₂R¹², COR¹¹ or NHR¹¹ wherein R¹¹and R¹² are as defined hereinbefore and/or wherein any of saidheterocyclic groups is benzo-fused; or R¹ is phenyl substituted by oneor more substituents selected from: CF₃, —OCF₃, —SO₂R¹², —COR¹¹, —CO₂R¹¹wherein R¹¹ and R¹² are as defined hereinbefore; R² is C₁ to C₆ alkyl;R¹³ is OR³; R³ is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl,i-butyl or t-butyl alkyl optionally substituted with one or twosubstituents selected from cyclopropyl, cyclobutyl, hydroxy, methoxy,ethoxy, benzyloxy, phenyl, benzyl, fu ran-3-yl,tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, pyridin-2-yl,pyridin-3-yl or NR⁵R⁶ wherein R⁵ and R⁶ are each independently selectedfrom H and C₁ to C₂ alkyl; R⁴ is a piperazin-1-ylsulphonyl group havinga substituent, R¹⁰ at the 4-position of the piperazinyl group whereinsaid piperazinyl group is optionally substituted with one or two C₁ toC₄ alkyl groups and is optionally in the form of its 4-N-oxide; and R¹⁰is H, C₁ to C₃ alkyl optionally substituted with one or two substituentsselected from hydroxy, NR⁵R⁶, CONR⁵R⁶ wherein R⁵ and R⁶ are eachindependently selected from H, C₁ to C₄ alkyl and C₃ alkenyl.
 4. Acompound according to claim 3 wherein R¹ is —(CH₂)_(n)(C₃—C₅)cycloalkylwherein n is 0, 1, 2 or 3; or R¹ is methyl, ethyl, iso-propyl orn-propyl substituted by one or more C₁ to C₄ alkoxy substituents whereinsaid alkoxy substituent may be directly attached to any C-atom withinthe ethyl, iso-propyl or n-propyl groups; or R¹ is a C₄ alkyl groupselected from i-, n-, sec- or t-butyl optionally substituted by one ormore substituents selected from C₁ to C₄ alkoxy or C₃ to C₄ cycloalkyl;R² is C₁ to C₄ alkyl; R¹³ is OR³ wherein R³ is C₁ to C₄ alkyl optionallysubstituted with one or two C₁ to C₄ alkoxy substituents wherein said C₁to C₄ alkyl and C₁ to C₄ alkoxy groups may optionally be terminated by ahaloalkyl group such as CF₃; R⁴ is a piperazin-1-ylsulphonyl grouphaving a single substituent, R¹⁰ at the 4-position of the piperazinylgroup and is optionally in the form of its 4-N-oxide and wherein R¹⁰ ismethyl or ethyl.
 5. A compound according to claim 4 having the generalformula (IA) or (IB):

wherein R¹ is —(CH₂)_(n)(C₃—C₄)cycloalkyl wherein n is 1 or 2; or R¹ is—(CH₂)_(n)(C₃-C₅)cycloalkyl wherein n is 0; or R¹ is—(CH₂)_(n)(C₅)Cycloalkyl wherein n is 1; or R¹ is methyl, ethyl,i-propyl or n-propyl substituted by methoxy, ethoxy, n-propoxy ori-propoxy wherein said alkoxy substituent may be directly attached toany C-atom within the ethyl, iso-propyl or n-propyl groups; or R¹ is i-,n-, sec- or t-butyl; R² is C₂ to C₄ alkyl; R¹³ is OR³ wherein the R³alkyl group is methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl,sec-butyl or t-butyl optionally substituted with one or two methoxy,ethoxy, n-propoxy or i-propoxy substituents; and R⁴ is a 4-methyl or4-ethylpiperazin-1-ylsulphonyl group.
 6. A compound according to claim 5having the general formula (IB):

wherein R¹ is —(CH₂)_(n)(C₃-C₄)cycloalkyl wherein n is 1 or 2; or R¹ is—(CH₂)_(n)(C₃—C₅)cycloalkyl wherein n is 0; or R¹ is—(CH₂)_(n)(C₅)cycloalkyl wherein n is 1; or R¹ is methyl, ethyl,i-propyl or n-propyl substituted by methoxy, ethoxy, n-propoxy ori-propoxy wherein said alkoxy substituent may be directly attached toany C-atom within the ethyl, iso-propyl or n-propyl groups; or R¹ is i-,n-, sec- or t-butyl; R² is C₂ to C₄ alkyl; R¹³ is OR³ wherein the R³alkyl group is methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl,sec-butyl or t-butyl optionally substituted with one or two methoxy,ethoxy, n-propoxy or i-propoxy substituents; and R⁴ is a 4-methyl or4-ethylpiperazin-1-ylsulphonyl group.
 7. A compound according to any ofclaims 1 to 4 selected from:5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-methoxyethyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-methoxyethyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-(sec-Butyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-(iso-Butyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-(Cyclopropylmethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-(Cyclobutylmethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxy-1-methylethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-(methylamino)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-(2-Dimethylaminoethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-dimethylaminoethyl-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-{2-[Acetyl(methyl)amino]ethyl}-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxypyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-(1-Acetylazetidin-3-yl)-5-[2-n-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Benzyloxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-iso-Butoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethanol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxypyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethanol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-iso-propoxypyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[(S)-2-sec-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethanol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[(R)-2-sec-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethanol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-{(pyridin-2-yl)methyl}pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-sec-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-Cyclobutylmethyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(S)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(R)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(S)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(R)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-hydroxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-(2-Dimethylaminoethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-iso-Butyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-iso-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-Cyclobutylmethyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-(dimethylamino)-2-oxoethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-{2-[methyl(methylsulphonyl)amino]ethyl}-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-Cyclobutylpropylmethyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-n-Butyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-n-Butoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-(2-Ethoxyethyl)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(3-methoxypropyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(S)-(2-methoxypropyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(R)-(2-methoxypropyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,2-(S)-sec-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneor2-(R)-sec-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneand pharmaceutically acceptable salts or polymorphs thereof.
 8. Apharmaceutical composition comprising a compound of formula (I), (IA) or(IB) as defined in any of claims 1 to 7, or a pharmaceuticallyacceptable salt or polymorph thereof, or a pharmaceutically acceptablesolvate or pro-drug thereof according to any of the preceding claims,together with a pharmaceutically acceptable diluent or carrier.
 9. Aveterinary formulation comprising a compound of formula (I), (IA) or(IB) as defined in any of claims 1 to 7, or a veterinarily acceptablesalt or polymorph thereof, or a veterinarily acceptable solvate orpro-drug thereof according to any of the preceding claims, together witha veterinarily acceptable diluent or carrier.
 10. A compound of formula(I), (IA) or (IB), or a pharmaceutically acceptable salt or polymorphthereof, or a pharmaceutically acceptable solvate or pro-drug thereofaccording to any claims 1 to 7, or a pharmaceutical compositionaccording to claim 8 containing any of the foregoing, for use as a humanmedicament.
 11. A compound of formula (I), (IA) or (IB), or aveterinarily acceptable salt or polymorph thereof, or a veterinarilyacceptable solvate or pro-drug thereof according to any of claims 1 to7, or a veterinary formulation according to claim 9 containing any ofthe foregoing, for use as an animal medicament.
 12. The use of acompound of formula (I), (IA) or (IB), or a pharmaceutically acceptablesalt or polymorph thereof, or a pharmaceutically acceptable solvate orpro-drug thereof according to any of claims 1 to 7, for the manufactureof a human medicament for the curative or prophylactic treatment of amedical condition for which a cGMP PDE5 inhibitor is indicated.
 13. Theuse of a compound of formula (I), (IA) or (IB), or a veterinarilyacceptable salt or polymorph thereof, or a veterinarily acceptablesolvate or pro-drug thereof according to any of claims 1 to 7, for themanufacture of an animal medicament for the curative, palliative orprophylactic treatment of a medical condition for which a cGMP PDE5inhibitor is indicated.
 14. The use of a compound of formula (I), (IA)or (IB), or a pharmaceutically acceptable salt or polymorph thereof, ora pharmaceutically acceptable solvate or pro-drug thereof according toany of claims 1 to 7, for the manufacture of a human medicament for thecurative, palliative or prophylactic treatment of male erectiledysfunction (MED), impotence, female sexual dysfunction (FSD), clitoraldysfunction, female hypoactive sexual desire disorder, female sexualarousal disorder, female sexual pain disorder or female sexual orgasmicdysfunction (FSOD).
 15. The use of a compound of formula (I), (IA) or(IB), or a veterinarily acceptable salt or polymorph thereof, or aveterinarily acceptable solvate or pro-drug thereof according to any ofclaims 1 to 7, for the manufacture of an animal medicament for thecurative, palliative or prophylactic treatment of male erectiledysfunction (MED), impotence, female sexual dysfunction (FSD), clitoraldysfunction, female hypoactive sexual desire disorder, female sexualarousal disorder, female sexual pain disorder or female sexual orgasmicdysfunction (FSOD)
 16. A method of treating or preventing a medicalcondition for which a cGMP PDE5 inhibitor is indicated, in a mammal(including a human being), which comprises administering to said mammala therapeutically effective amount of a compound of general formula (I),(IA) or (IB), or a pharmaceutically or veterinarily acceptable salt orpolymorph thereof, or a pharmaceutically or veterinarily acceptablesolvate or pro-drug thereof according to any of claims 1 to 7, or apharmaceutical composition according to claim 8 or a veterinaryformulation according to claim 9 containing any of the foregoing.
 17. Amethod of treating or preventing male erectile dysfunction (MED),impotence, female sexual dysfunction (FSD), clitoral dysfunction, femalehypoactive sexual desire disorder, female sexual arousal disorder,female sexual pain disorder or female sexual orgasmic dysfunction (FSOD)in a mammal (including a human being), which comprises administering tosaid mammal a therapeutically effective amount of a compound of generalformula (I), (IA) or (IB), or a pharmaceutically or veterinarilyacceptable salt or polymorph thereof, or a pharmaceutically orveterinarily acceptable solvate or pro-drug thereof according to any ofclaims 1 to 7, or a pharmaceutical composition according to claim 8 or aveterinary formulation according to claim 9 containing any of theforegoing.
 18. A compound of the formula (IX):

wherein R^(P) is R¹³ as defined in claim 1 or R^(P) is X which is aleaving group.
 19. A process for the preparation of a compound offormula (I):

wherein R¹, R², R¹³ and R⁴ are as defined in claim 1, which processcomprises cyclisation of a compound of formula (IX):

wherein R^(P) is R¹³ or R^(P) is X which is a leaving group and R¹, R²,R⁴ and R¹³ are as defined in claim 1 wherein said cyclisation reactionis optionally followed by formation of a pharmaceutically orveterinarily acceptable salt of the required product or apharmaceutically or veterinarily acceptable solvate or pro-drug of therequired product.
 20. A process according to claim 19 wherein thecyclisation reaction is base-mediated, using an alkali metal salt of asterically hindered alcohol or amine.
 21. A process for the preparationof compounds of the general formula (IX) via a coupling reaction betweencompounds of the general formula (VII):

wherein R¹ and R² are as defined for compounds of the formula (I) inclaim 1 and compounds of the formula (X):

wherein R¹³ and R⁴ are as previously defined for formula (I) in claim 1.22. A process according to claim 21 wherein the coupling reaction iscarried out using conventional amide bond-forming techniques. 23.Compounds of the general formula (VII);

wherein R¹ and R² are as defined for compounds of the formula (I) inclaim
 1. 24. Compounds of the general formula (VIIB)

wherein R¹ is methoxyethyl and R² is ethyl.
 25. Compounds of the generalformula (X):

wherein R¹³ is OR³ and wherein R³ is ethyl and wherein R⁴ isethylpiperazin-1-ylsulphonyl.
 26. A process for the preparation of acompound of formula (XB) or a salt thereof from a compound of formula(XIV):

(a) for a compound formula (XB) wherein X is arylsulfonyloxy, C₁-C₄alkylsulfonyloxy, C₁-C₄ perfluoroalkylsulfonyloxy, aryloxy, C₁-C₄perfluoroalkanoyloxy, C₁-C₄ alkanoyloxy, quarternary ammonium C₁-C₄alkylsulfonyloxy or halosulfonyloxy, comprising reacting a compound offormula (XIV) wherein Q and W are OH in the presence of an appropriatesulphonylating, arylating or acylating agent of X; (b) for a compound offormula (XB) wherein X is Cl, comprising reaction of a compound offormula (XIV) wherein Q is Cl and W is P and P is a protecting group,with a deprotecting agent; (c) for a compound of formula (XB) wherein Xis diazonium, comprising reacting a compound of formula (XIV) wherein Qis NH₂, W is OH with nitrous acid; (d) for a compound of formula (XB)wherein X is (diarylsulfonyl)amino comprising reacting a compound offormula (XIV) wherein Q=NH₂ and W=OH in the presence of an appropriatesulphonylating agent for X; (e) for a compound of formula (XB) wherein Xis OR³ wherein OR³ is a C₁-C₆ alkoxy, group comprising reacting acompound of formula (XVI) wherein W is P where P is a protecting groupand Q is a C₁-C₆ primary or secondary alkoxy group with a deprotectingagent.
 27. A process for the preparation of compounds of formula (XIV)as shown in claim 26 from compounds of formula (XV):

wherein D is Cl or Br and P is a protecting group, (a) wherein forcompounds of compound (XIV) wherein Q is OH and W is OH, comprisingreacting a compound of formula (XV) with a hydrolising agent andoptionally a further deprotecting agent where P is not deprotected bythe hydrolysing agent; (b) wherein for compounds of formula (XIV)wherein Q is NH₂ and W is OH, comprising reacting a compound of formula(XV) with an ammoniating agent to form an intermediate compound offormula (XIV) wherein Q is NH₂ and W is P (a protecting group) and thereacting said intermediate (XIV) with a deprotecting agent; and (c)wherein for compounds of compound (XIV) wherein Q is OR³ which is a C₁₋₆alkoxy and W is P, comprising reacting a compound of formula (XV) in thepresence of ⁻OR³;
 28. A process for the preparation of a compound offormula (XV) according to claim 27 comprising reaction of compounds offormula (XVI) in the presence of N—R¹⁰ piperazin-1-ylsulphonyl, whereinR¹⁰ is as defined in claim 1:

wherein D and P are as defined in claim
 27. 29. A process for thepreparation of a compound of formula (XVI) according to claim 28comprising reacting a compound of formula (XX) with a chlorinating orbrominating agent:

wherein P is as defined in claim
 27. 30. A process according to claim 29for preparation of a compound of formula (XX) comprising reacting acompound of formula (XVII) in the presence of an agent which will form aprotecting group (P) on the carboxylic acid:


31. A process according to claim 30 for the preparation of a compound offormula (XVII) comprising reacting 2-hydroxynicotinic acid or a saltthereof in the presence of SO₃ in a solvent.
 32. A process according toclaim 31 wherein the SO₃ is in an organic solvent, an aprotic solvent, amineral acid, or a liquid carboxylic acid.
 33. A process according toany one of claims 26 to 32 wherein the compounds of formulae (XB), (XIV)and (XV) are respectively:

wherein X is a C₁₋₆ alkoxy group, Q and W are as defined in claims 26and 27, and the compounds (XB) and (XIV) are formed according to theprocesses of claim 26(e) and claim 27(c) respectively and compound (XV)is formed according to the process of claim 28 by reacting compound(XVI) with N-ethyl piperazine or a salt thereof.
 34. A process accordingto claim 33 wherein X is OEt and the compound (XB) is formed by reactionof compound (XIV) with a deprotecting agent, and compound (XIV) isformed by reaction of compound (XV) in the presence of OEt.
 35. Aprocess according to claims 33 or 34 wherein compound (XX) is formed byreacting compound (XVII) or a salt thereof with ethanol to form aprotecting group, OEt.
 36. A process for the preparation of a compoundof formula (I):

wherein R¹, R², and R⁴ are as defined in claim 1 and R¹³ is OR³ asdefined in claim 1, which process comprises conversion of a compound offormula (XXX):

wherein X is a leaving group and R¹, R² and R⁴ are as defined in claim 1and wherein said conversion reaction is optionally followed by formationof a pharmaceutically or veterinarily acceptable salt of the requiredproduct or a pharmaceutically or veterinarily acceptable solvate orpro-drug of the required product.
 37. A compound of the general formula(XXX):

wherein R¹, R² and R⁴ are as defined in claim 1 and wherein X is aleaving group.
 38. A process for the preparation of a compound of thegeneral formula (I) from a compound of general formula (IXB) via: i)cyclisation (IXB to XXX) followed by displacement (XXX to I); ii)cyclisation (IXCa to XXX) followed by displacement (XXX to I); iii)displacement (IXB to IXC) followed by cyclisation (IXC to I); iv)displacement (IXCa to IXC) followed by cyclisation (IXC to I) wherein incompounds (XXX) and (IXCa) have the general formulae:

wherein R¹, R², R⁴ and X are as defined herein before and OR^(3a) is analkoxy group which is different from and displaceable by the desired OR³group on the final compounds of general formula (I) and wherein R^(3a)selected from C₁ to C₆ alkyl optionally substituted; or v) directcyclisation of (IXB) to (I).